What Mouse Mutants Teach Us About Extracellular Matrix Function

Annu. Rev. Cell Dev. Biol. 2006.22:591-621. Downloaded from arjournals.annualreviews.org by Washington University Library, Danforth Campus on 12/01/07. For personal use only.

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What Mouse Mutants Teach Us About Extracellular Matrix Function ´ 1 Kyle R. Legate,1 I. Nakchbandi,1,2 A. Aszodi, and R. Fässler1 1

Department of Molecular Medicine, Max Planck Institute for Biochemistry, 82152 Martinsried, Germany; email: [email protected], [email protected], [email protected]

2

Institute for Immunology, University of Heidelberg, 69120 Heidelberg, Germany; email: [email protected]

Annu. Rev. Cell Dev. Biol. 2006. 22:591–621

Key Words

First published online as a Review in Advance on July 12, 2006

gene targeting, transgenics, connective tissue, basement membrane, mouse development

The Annual Review of Cell and Developmental Biology is online at http://cellbio.annualreviews.org This article’s doi: 10.1146/annurev.cellbio.22.010305.104258 c 2006 by Annual Reviews. Copyright All rights reserved 1081-0706/06/1110-0591$20.00

Abstract For many years the extracellular matrix was viewed as a benign scaffold for arranging cells within connective tissues, but it is now being redefined as a dynamic, mobile, and flexible key player in defining cellular behavior. Gene targeting, transgene expression, and spontaneous mutations of extracellular matrix proteins in mice have greatly accelerated our mechanistic view of the structural and instructive functions of the extracellular matrix in developmental and regenerative processes. This review summarizes the phenotypes of genetic mouse models carrying mutations in extracellular matrix proteins, with specific emphasis on recent advances. The application of reverse genetics has demonstrated the multifunctionality of matrix proteins in a biological context and, in addition, has brought a novel perspective to the understanding of human pathologies.

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Contents INTRODUCTION . . . . . . . . . . . . . . . . . STRUCTURAL FUNCTIONS OF ECM MOLECULES . . . . . . . . . . . . Proteins Involved in the Stability of Connective Tissues . . . . . . . . . . . . The Role of ECM Components in Basement Membrane Integrity . . . . . . . . . . . . . . . . . . . . . . ECM COMPONENTS AND SIGNALING . . . . . . . . . . . . . . . . . . . . Collagens and Signaling . . . . . . . . . . Proteoglycans and Growth Factor Signaling. . . . . . . . . . . . . . . . . . . . . . Microfibrils and Growth Factor Signaling. . . . . . . . . . . . . . . . . . . . . . Laminins in Signaling . . . . . . . . . . . . Fibronectin . . . . . . . . . . . . . . . . . . . . . . COLLAGEN-DERIVED MATRICRYPTINS AND ANGIOGENESIS . . . . . . . . . . . . . . . MATRICELLULAR PROTEINS . . . CONCLUDING REMARKS . . . . . . .

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INTRODUCTION

Basement membranes (BMs): specialized extracellular matrices forming dense, sheet-like structures underneath or around cells; they serve as selective barriers and provide structural scaffolds and environmental cues that regulate cellular behavior

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In multicellular organisms, the extracellular matrix (ECM) provides physical support to tissues and organs by occupying the space between cells. The ECM is present in every tissue but is most highly enriched in connective tissue and basement membranes (BM). The ECM is a heterogeneous mixture of water, saccharides, and various protein components traditionally classified into four categories: collagens, proteoglycans (PGs), noncollagenous glycoproteins, and elastins. Upon deposition, the protein constituents are organized into three-dimensional tissue-specific meshworks, which establish the structural environment in which cells are embedded. The structure is highly dynamic and undergoes constant remodeling controlled by a delicate balance between ECM synthesis and degradation. The ECM, however, not only provides Aszódi et al.

a physical framework for cells but also influences a number of cellular functions via two basic mechanisms. First, the ECM serves as storage depot for transient components like growth factors, cytokines, chemokines, and enzymes. Resident proteins bind to some of these molecules and modulate their activity, bioavailability, or presentation to cell surface receptors. Second, most, if not all, matrix proteins directly interact with cellular receptors affecting cell adhesion and migration. The active interplay between cells and the ECM culminates in intracellular events associated with signal transduction cascades, which in turn regulate the expression of genes necessary for cell differentiation, proliferation, and survival. Although the contributions of structural biology, biochemistry, and cell biology to ECM research are enormous, extensive crosslinking of components and their high degree of posttranslational modification make it difficult to study their functions in vitro. Genetic approaches are the most effective tools with which to elucidate the complex functions of ECM constituents in vivo. The identification of mutant ECM genes by means of forward genetics in human patients or in spontaneous mouse models has significantly advanced our understanding of connective tissue pathologies, but gene targeting approaches or overexpression of transgenes in mice are more powerful techniques with which to study systematically the role of the ECM in developmental and pathological processes. To date, more than 70 genes encoding ECM proteins have been ablated in mice (see Supplemental Table 1; follow the Supplemental Material link from the Annual Reviews home page at http://www.annualreviews.org); together with mouse strains carrying naturally occurring mutations or overexpressing mutant polypeptides, such genes give exciting insights into the diverse biological functions of the ECM. In this review, we discuss the recent advances that genetic manipulations in mice have revealed regarding novel mechanical and signaling roles of ECM components during development and disease.

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STRUCTURAL FUNCTIONS OF ECM MOLECULES The structural integrity of extracellular matrices is defined by (a) their macromolecular composition, (b) the complex interactions among the resident proteins, and (c) the capability of these ECM molecules to assemble a highly organized, three-dimensional architecture. In most tissues the primary scaffold is made of collagen fibrils or networks that entrap various PGs and glycoproteins. Together they form specific supramolecular assemblies to fulfill the various mechanical requirements of connective tissues and BMs.

Proteins Involved in the Stability of Connective Tissues Collagen fibrils. All collagens consist of three polypeptide chains (α chains) and possess characteristic triple-helical collagenous (COL) as well as noncollagenous (NC) domains. To date, 27 collagen types have been reported in vertebrates; these can be grouped into nine families on the basis of their supramolecular assemblies and other features (Myllyharju & Kivirikko 2004). Among them, fibril-forming collagens assemble into long, highly ordered polymers that can withstand high tensile forces. Fibrillar collagens are synthesized as procollagen molecules composed of a long COL domain flanked by globular propeptides at the N and C termini. Upon secretion, the propeptides are usually cleaved, and the collagen monomers form short fibrillar intermediates that subsequently grow into mature fibrils through linear and lateral fusion events. Although fibrillogenesis is driven primarily by the COL domain, fibrillar growth and interfibrillar spacing are influenced by various ECM molecules, which define the final architecture of collagen fibrils in different tissues (Canty & Kadler 2005). The family of fibrillar collagens includes the abundant types—I, II, and III—and the quantitatively minor types—V and XI. Collagen types I, III, and V have broad distribution

in the body, whereas collagens II and XI are mainly restricted to cartilage, vitreous body, and the tectorial membrane of the inner ear. Structural and null mutations in these collagens cause a spectrum of human disorders such as osteogenesis imperfecta, familial arterial aneurism, certain subtypes of Ehlers-Danlos syndrome, and various chondrodysplasias, underscoring the critical contribution of collagen fibrils to tissue function (Myllyharju & Kivirikko 2004). Numerous mutant mouse strains that recapitulate the hu´ et al. man phenotypes are available (Aszodi 1998, Myllyharju & Kivirikko 2004, Reginato & Olsen 2002). Here, we focus on those mutant mice that give insight into the complex scenario of fibril formation and stabilization. The heterotrimeric collagens V (α12 α2) and XI (α1α2α3) copolymerize with collagens I and II, respectively, to form heterotypic fibrils. In vitro fibril assembly experiments showed that the minor components of the fibrils regulate the diameter of the fibrils by projecting their retained N-propeptides onto the fibril surface, thereby limiting the addition of new monomers through steric and/or electrostatic hindrance (Blaschke et al. 2000, Linsenmayer et al. 1993). Consistent with these in vitro findings, mice carrying a targeted mutation in the N-terminal portion of the α2(V) chain (Col5a2pN /pN ) display thick collagen I fibrils in the corneal stroma (Andrikopoulos et al. 1995). In addition, these mice have fragile skin containing a reduced number of loosely packed fibrils. Further analysis of the skin revealed that this mutation severely impairs the intracellular assembly and/or secretion of α1(V)2 α2(V) heterotrimers, and predominantly α1(V)3 homotrimers are deposited into the matrix (Chanut-Delalande et al. 2004). These homotrimers, however, do not incorporate into collagen I–containing fibrils and form distinct, thin filaments. As a consequence, the initiation of heterotypic fibril assembly is compromised, leading to fewer, disorganized collagen fibrils in the dermal matrix. The critical role of collagen V in heterotypic

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Figure 1 Regulation of fibril formation by type V collagen. (a) In the normal situation (Col5a1+/+ ), collagen V and collagen I copolymerize into heterotypic fibrils through a regulated fibril assembly process. Primary fibrils nucleated in the presence of collagen V form short intermediates, which subsequently grow by linear and lateral fusion events. As the retained N-terminal propeptide of collagen V reaches a certain concentration at the fibrillar surface, fibril growth may stop, and new fibril initiation becomes favorable. This mechanism leads to a population of fibrils with relatively consistent diameters. (b) When collagen V is missing owing to α1(V) chain deficiency (Col5a1−/− ), fibril initiation is impaired, and only a few morphologically abnormal fibrils can form via unregulated self-assembly of collagen I molecules. In the case of collagen V haploinsufficiency (Col5a1+/− ), fewer fibrils are nucleated and form into either normal or thick, irregular fibrils, depending on the amount of collagen V molecules incorporated into the fibrils. Excess collagen I molecules may self-aggregate to form abnormal fibrils. Adapted from Wenstrup et al. 2004.

fibril formation was clearly demonstrated in mice lacking the collagen α1(V) chain (Figure 1) (Wenstrup et al. 2004). The Col5a1−/− animals fail to produce collagen V and die at embryonic day 10.5 (E10.5) from cardiovascular failure. The lethal phenotype is accompanied by the complete lack of collagen I–containing fibrils in the mesenchyme and the presence of a few morphologically abnormal fibrils in the vicinity of the ectodermal BM. In contrast, heterozygous mice (Col5a1+/− ) survive but show both normal and abnormal populations of dermal collagen fibrils associated with a 50% decrease in fibrillar density and collagen content. On the basis of these observations, the primary role 594

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of type V collagen is to control early fibril initiation. Collagen fibrils incorporating collagen V nucleate and grow through a regulated fibril assembly process, whereas collagen I molecules not associated with collagen V can undergo only unregulated self-aggregation, leading to a limited number of morphologically abnormal fibrils. That minor collagens are critical regulators of fibrillogenesis in vivo has been corroborated in collagen XI–mutant mice. The naturally occurring cho/cho mice harboring a premature stop codon at the N-terminal region of the α1(XI) chain display a reduced number of abnormally thick fibrils in the cartilage matrix, leading to a severely


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disorganized growth plate, and die at birth with short limbs and cleft palate (Li et al. 1995). Mice lacking Col11a2 (Li et al. 2001) may still form α1(XI)3 homotrimers or heterotrimers composed of α1(XI) and α3(XI) chains. Such mice show a phenotype milder than that of the cho/cho mice, characterized by the formation of electron-dense bundles in the cartilage matrix, suggesting that the α2(XI) chain regulates the lateral association of individual collagen fibrils. The heterotrimeric (α1α2α3) collagen IX and the homotrimeric collagen XII are structurally related nonfibrillar collagens associated with the surface of type II and type I collagen fibrils, respectively. Mice with a targeted inactivation of the Col9a1 gene develop a relatively mild phenotype characterized by earlyonset osteoarthritis, without overt morphological alterations of cartilage fibrils (Fässler et al. 1994), and show progressive hearing loss, with disorganized fibrillar ultrastructure in the tectorial membrane (Asamura et al. 2005). Transgenic mice expressing truncated collagen XII molecules show fibrillar abnormalities in only a few tissues, such as periodontal ligaments and the skin (Reichenberger et al. 2000). Together, these data show that collagens IX and XII may play a role in fibrillar collagen organization and tissue integrity at specific anatomic locations. Elastic fibers and microfibrils. Elastic fibers, composed of an elastin core and the surrounding microfibrillar network, provide elasticity and resilience to flexible tissues. During elastogenesis, soluble precursor tropoelastin molecules are deposited into a preformed microfibrillar matrix and are subsequently cross-linked to form insoluble elastin polymers. Microfibrils, which are also present in some flexible tissues in which elastin is absent, contain a large number of integrated and associated components, including fibrillin-1 and -2, fibulins, latent transforming growth factor beta (TGF-β)-binding proteins (LTBPs), and emilins (Kielty et al. 2002). Elastic fiber abnormalities are asso-

ciated with several pathologies, and mouse models that assist in our understanding of human elastic tissue diseases have been developed in recent years. In humans, elastin haploinsufficiency causes supravalvular aortic stenosis (SVAS), an obstructive vascular disorder characterized by the narrowing of large arteries. Both heterozygous mice carrying an elastin gene null mutation (Eln+/− ) and SVAS patients show a thickened aortic wall associated with an increased number of elastic lamellae and vascular smooth muscle cells (SMCs), suggesting that a decreased elastin level induces a developmental compensation mechanism that leads to the formation of more elastic rings (Li et al. 1998b). Elastin-null mice (Eln−/− ) display normal arterial development during embryogenesis; however, they die shortly after birth from arterial occlusion caused by excessive proliferation and subendothelial accumulation of vascular SMCs (Li et al. 1998a). Therefore, elastin apparently is important for late arterial morphogenesis regulating proliferation, migration, and organization of vascular SMCs (Karnik et al. 2003, Li et al. 1998a). Fibrillin-1 and -2 are cysteine-rich glycoproteins that polymerize into a structure resembling beads on a string and, upon lateral association of the individual polymers, provide the structural backbone of the microfibrillar lattice (Ramirez et al. 2004). In humans, fibrillin-1 mutations give rise to Marfan syndrome (MFS), a pleiotropic disorder with cardiovascular, ocular, and skeletal abnormalities. The cardiovascular complications, the major source of mortality and morbidity of MFS, include aortic aneurysm and dissection as well as mitral valve prolapse (Milewicz et al. 2000). Mutations in human fibrillin-2 cause congenital contractural arachnodactyly, an MFS-related disorder with primarily musculoskeletal manifestations (Milewicz et al. 2000). Mouse models carrying hypomorphic (i.e., involving reduced expression of protein) or dominant-negative fibrillin-1 mutations develop aortic ruptures at various stages postnatally and recapitulate the early


Growth plate: a specialized cartilage structure in which linear growth takes place during endochondral bone formation. In the growth plate, the chondrocytes are organized into vertical columns and form horizontal zones according to their differentiation stage TGF-β: transforming growth factor beta SMCs: smooth muscle cells

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BMP: bone morphogenetic protein


Integrins: heterodimeric (αβ) transmembrane cell adhesion molecules that mediate cell-matrix interactions

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and late lethal forms of MFS, indicating that gene dosage effects or the nature of the fibrillin-1 mutation influence the severity of MFS (Pereira et al. 1997, 1999; Judge et al. 2004). Surprisingly, these mice show normal elastic fiber morphology at the nondamaged aortic areas and in unaffected tissues, suggesting that the primary role of fibrillin-1 is to maintain tissue integrity (Ramirez et al. 2004). However, this view is being challenged because mice lacking fibrillin-1 (Fbn1−/− ) show perturbed maturation of the neonatal aortic wall and die approximately 14 days after birth from the disruption of mechanically stressed elastic tissues (Carta et al. 2006). Mice lacking fibrillin-2 (Fbn2−/− ) are viable without any sign of vascular defects but display syndactyly owing to defective bone morphogenetic protein (BMP) signaling (see below) (Arteaga-Solis et al. 2001). On the other hand, fibrillin-1/fibrillin-2 double deficiency causes embryonic lethality associated with delayed/impaired elastogenesis (Carta et al. 2006). Therefore, fibrillin-1 and -2 have overlapping functions in early elastic fiber assembly; furthermore, fibrillin-1 has a dual role in regulating aortic wall development and in supporting structural integrity of force-bearing elastic tissues. Fibulin-5 (Fbl-5) is a modular glycoprotein that links elastic fibers to cells through binding both tropoelastin and integrins (Nakamura et al. 2002, Yanagisawa et al. 2002). This bridging function predicts a role for Fbl-5 in elastogenesis. Indeed, Fbl5−/− mice display disorganized and fragmented elastic fibers, leading to lung emphysema, loose skin, and vascular abnormalities (Nakamura et al. 2002, Yanagisawa et al. 2002). This phenotype resembles the clinical manifestations of a severe autosomalrecessive form of cutis laxa, a disorder that is characterized by loose skin and pulmonary emphysema and is caused by a homozygous missense mutation in the FBL5 gene (Loeys et al. 2002). LTBPs 1–4 are fibrillin-related molecules with two putative functions: as structural comAszódi et al.

ponents of the ECM and as modulators of TGF-β availability (see below) (Hyytiainen et al. 2004). Among the mouse models for LTBPs, only LTBP-4 hypomorphic mice display a clear structural defect. These mice develop pulmonary emphysema and rectal prolapse associated with fragmented elastic fibers in the lung and colon (Sterner-Kock et al. 2002), suggesting that LTBP-4 plays a role in the development of elastic fibers via interactions with microfibrils in specific tissues. Emilin-1, which belongs to the emilin/ multimerin family of ECM proteins, is located at the interface of the elastin core and the microfibrils. Elastin, fibulin-5 (Zanetti et al. 2004), and β1 integrin (Spessotto et al. 2003) bind to emilin-1, suggesting that emilin-1 has multiple roles in elastogenesis, in the maintenance of proper elastic fiber organization, and in anchorage-dependent cellular functions. Emilin-1 knockout mice have a normal life span but show several mild alterations in the skin and aorta, including abnormal elastic fibers, diminished cell–elastic lamellae connections, and cell morphological defects (Zanetti et al. 2004). Proteoglycans in tissue stability. PGs consist of a core protein covalently linked to glycosaminoglycan (GAG) side chains. Glycosaminoglycans are sulfated oligosaccharides composed of repeated disaccharide units of dermatan sulfate (DS), heparan sulfate (HS)/heparin, chondroitin sulfate (CS), or keratan sulfate (KS). PGs play an essential role in the hydration and osmotic properties of the matrix but are predicted to serve additional functions through interactions with various matrix components, growth factors, and cell surface receptors. Hyalectans are large CS-containing PGs that form aggregates with hyaluronan, an unsulfated GAG polymer made of repeating disaccharide units. The family consists of four members with different tissue distributions: Versican is the most ubiquitously expressed hyalectan, and aggrecan is predominant in cartilage, whereas neurocan and


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brevican are restricted to the brain. Although all hyalectans are believed to be important in ECM organization, knockout experiments support this hypothesis only for aggrecan and versican. Mice homozygous for an insertional mutation in the Gspg2 gene encoding versican die at approximately E10.5 from severe heart segmentation problems associated with impaired matrix swelling of the endocardial cushions and with failure in cell migration (Mjaatvedt et al. 1998). Mice lacking hyaluronan synthase 2 develop a similar phenotype (Camenisch et al. 2000), suggesting that the versican-hyaluronan interaction is essential for generating an ECM environment conducive to cell migration during cardiac development. In cartilage, the hydrated nature of aggrecan-hyaluronan aggregates provides the tissue with resilience and resistance against compressive forces. The lack of aggrecan in the spontaneous mutant cmd/cmd mouse strain leads to perinatal lethality owing to cleft palate and severe impairment of endochondral bone formation; such impairment is characterized by compression of the cartilage ECM, disorganization of the growth plate, and alterations in the expression pattern of cartilage-specific genes (Wai et al. 1998, Watanabe et al. 1994). In contrast to aggrecan- and versican-null mutations, mice lacking both neurocan and brevican are viable and show no overt morphological alterations in the central nervous system (CNS) (Rauch et al. 2005). However, neurocan or brevican deficiency impairs hippocampal long-term potentiation, suggesting a role of these hyalectans in synaptic plasticity (Brakebusch et al. 2002, Zhou et al. 2001). The family of small leucine-rich proteoglycans (SLRPs) is currently thought to be composed of 13 members. SLRPs are characterized by a relatively small core protein containing a varying number of leucinerich repeat (LRR) units that are flanked by disulfide-bonded, cysteine-rich domains at the N and C termini (Ameye & Young 2002). SLRPs such as decorin, biglycan, and fibromodulin are widely distributed in the body, whereas others like lumican, keratocan, or

mimecan have a more restricted expression pattern. Several SLRPs bind to fibrillar collagens via the LRR domain and regulate the assembly of collagen fibrils in vitro. Decorin, the most-studied SLRP, binds via its LLRs near the C terminus of individual collagen I fibrils, regulates lateral fusion, and maintains an even interfibrillar spacing via its DS side chain (Reed & Iozzo 2002). The distribution of SLRPs on collagen fibrils, their GAG moiety, their disulfide loops, and their potential multimerization have also been deemed to be important in fibril lateral assembly, orientation, and stability (Waddington et al. 2003). Mice lacking members of this family have type I collagen–containing fibrils with an irregular diameter and/or organization and develop a broad range of diseases (e.g., osteoporosis, osteoarthritis, Ehlers-Danlos syndrome, and various corneal diseases) owing to altered tissue mechanics or structure (Ameye & Young 2002, Kao & Liu 2002). Although the in vivo phenotypes of various SLRP knockouts confirm the significance of these PGs in collagen fibrillogenesis, the underlying mechanisms are still not completely understood. Perlecan is a heparan sulfate proteoglycan (HSPG) with a broad expression pattern. The core protein of perlecan consists of five distinct domains: Three HS chains are attached to the N-terminal domain I, and an additional chain is potentially localized to domain V. Perlecan-null (Hspg2−/− ) mice die at two stages: at E10.5–12.5 owing to BM defects and perinatally owing to respiratory failure (Arikawa-Hirasawa et al. 1999, Costell et al. 1999). Mutants that die at birth are dwarfed and show a severe cartilage defect. The growth plate is disorganized, and chondrocyte proliferation and differentiation and subsequent endochondral bone formation are impaired (Arikawa-Hirasawa et al. 1999, Costell et al. 1999). These defects may arise from a structurally altered ECM because the mutant cartilage contains fewer and shorter collagen fibrils (Costell et al. 1999). The mechanism behind the reduced collagen density is not clear, but perlecan may help


Endochondral bone formation: a basic mechanism of skeletogenesis characterized by the formation of a cartilaginous template that is subsequently replaced by bone LRR: leucine-rich repeat

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Matrix metalloproteinases (MMPs): a family of zinc-dependent proteinases involved in ECM turnover in both normal and diseased tissues Basement membrane (BM) zone: the basement membrane and associated region contiguous with the subjacent connective tissue

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to protect the collagen network from degradation by binding and regulating the activity of matrix metalloproteinases (MMPs) (Costell et al. 1999). The cartilage abnormalities of the Hspg2−/− mice resemble those seen in SilverHandmaker type dyssegmental dysplasia, a lethal autosomal-recessive skeletal syndrome in humans caused by functional null mutations in the perlecan gene (Arikawa-Hirasawa et al. 2001).

The Role of ECM Components in Basement Membrane Integrity BMs are composed primarily of collagen IV, laminins, nidogens, and perlecan. Additional components of BM zones include agrin, fibulins, fibronectin (Fn), and various nonfibrillar collagens. The fine structural architecture and the interaction repertoire among structural proteins and cell surface molecules in BM zones can be varied to fulfill tissue-specific requirements (Miner et al. 2004 and Yurchenco et al. 2004). Collagens modulate the integrity and function of basement membrane zones. The most abundant collagenous component of BMs is the network forming type IV collagen, which is composed of the heterotrimeric combination of six distinct α polypeptide chains. Although the major embryonic collagen IV isoform, α12 α2(IV), is expressed already at the blastocyst stage, mice with a targeted inactivation of the Col4a1/Col4a2 locus ¨ (Poschl et al. 2004) continue to develop until E9.5 and deposit BM-like sheets in the absence of any collagen IV isoforms. After E9.5, α12 α2(IV) deficiency leads to BM instability, resulting in the rupture of mechanically stressed BMs and Reichert’s membrane (RM)—a specialized BM that separates embryonic from maternal tissue—leading to death between E10.5–E11.5. Mice carrying a dominant-negative mutation in the Col4a1 gene, which prevents the secretion of collagen IV heterotrimers, also develop disrupted BMs and die at mid-gestation (Gould et al.

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2005). Heterozygous mice have reduced perinatal viability and cerebral hemorrhage, and some survivors have a porencephaly-like phenotype. Porencephaly is a rare neurogical disorder that is characterized by cerebral lesions and degenerative cavities caused by hemorrhaging, leading to disability and death in severe cases. Collagen IV may be among the predisposing factors for porencephaly because mutations in the COL4A1 gene were recently found in two affected families (Gould et al. 2005). Taken together, these findings indicate that a collagen IV network is not essential for the assembly of BM but is required to maintain its integrity under mechanical pressure. Mice carrying mutations for other BMzone collagens develop phenotypes at distinct anatomical locations, suggesting specialized roles for these collagens (reviewed in Gustafsson & Fässler 2000). For example, mice lacking the quantitatively minor α3 or α3/α4 collagen IV chains develop glomerulonephritis, recapitulating autosomal forms of Alport syndrome, whereas collagen VII deficiency leads to skin blistering resembling dystrophic epidermolysis bullosa in humans. Such analyses of various transgenic mouse strains have revealed a particularly important role of BM-zone collagens in muscle and eye development. Collagen VI is a beaded filament-forming collagen composed of three distinct α chains. It has been suggested to play a role in anchoring the BM of nonepithelial cells to the underlying matrix, attaching the collagen IV network to the components of the interstitium. Col6a1-null mice display muscular abnormalities such as irregular fiber diameter, fiber necrosis, and impaired contractile strengths of the muscle (Bonaldo et al. 1998, Irwin et al. 2003). The phenotype resembles Bethlem myopathy, an early-onset muscular disorder with autosomal-dominant inheritance, which is associated with mutations in the genes encoding collagen VI (Lampe & Bushby 2005). Collagen types XV and XVIII are examples of nearly ubiquitously expressed, highly glycosylated BM-zone collagens with


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tissue-restricted function. Mice lacking collagen XV are viable but suffer from progressive skeletal myopathy and cardiocascular defects (Eklund et al. 2001). BMs are apparently normal in mutants, suggesting that collagen XV is not required for BM assembly but is necessary for providing the linkage between cells and the surrounding ECM to maintain the mechanical stability of muscles and capillaries. Collagen XVIII deficiency in mice leads to various ocular defects, accompanied by BM abnormalities (reviewed in Marneros & Olsen 2005). The defects include decreased attachment of vitreous collagen fibrils into the BM covering the retinal surface; iris rupture; ciliary body atrophy; and age-dependent loss of vision, with impaired retinal pigment epithelial function. Most of these abnormalities are found in patients with Knobloch syndrome, an autosomal-recessive disorder caused by inactivation of mutations in the human COL18A1 gene (Suzuki et al. 2002). Defective BMs in Col18a1−/− mice, however, are not restricted to the eye: Thickened BMs have been observed in the choroid plexus, leading to dilation of the brain ventricles and increased, genetic background–dependent susceptibility to hydrocephalus (Utriainen et al. 2004). Thus, collagen XVIII evidently plays a role in BM structure and affects some epithelial functions via the regulation of cell-matrix interactions. Basement membrane glycoproteins: the laminin networks. Laminins are a family of 16 heterotrimeric (αβγ) glycoproteins generated by the combination of 5α, 4β, and 3γ chains. Polymeric laminin networks selfassociate to interact with ECM and cell surface molecules such as nidogen, perlecan, integrins, and α-dystroglycan. All BMs contain laminins, but the isoform distribution is regulated in a developmental and tissuespecific manner (Miner & Yurchenco 2004, Yurchenco et al. 2004). Here we refer to laminins using the new simplified nomenclature, which number the laminins with three Arabic numerals corresponding to the α, β,

and γ chains, respectively (Aumailley et al. 2005). Laminin-111 and laminin-511 are the two laminin isoforms present in the nascent BMs of peri-implantation embryos (Figure 2). Mice deficient in β1 or γ1 subunits die soon after implantation (at E5.5), have no detectable laminin trimers, and lack both embryonic BM (which separates the epiblast from the visceral endoderm) and Reichert’s membrane, confirming that laminins are the key molecular components initiating BM assembly (Miner et al. 2004, Smyth et al. 1999). The absence of embryonic BM– derived signals impairs endoderm differentiation, epiblast polarization, and the formation of proamniotic cavity. In contrast, α1- or α5null mice survive until E7 and E13.5–E17, respectively, indicating that laminin-111 and laminin-511 can partially compensate each other during early development (Miner & Li 2000; Miner et al. 1998, 2004). For instance, in α1-deficient mice, embryonic BM and the proamniotic cavity form, whereas the RM is missing (Miner et al. 2004). Furthermore, although transgenic overexpression of the laminin α5 subunit in α1-null mice extends viability up to E7.5 and allows the initiation of gastrulation, it cannot support RM formation (Miner et al. 2004). These studies reveal the critical role of laminin111 in Reichert’s membrane formation, but the question remains as to whether embryonic BM containing only laminin-511 could support development if the RM were unaffected. Interestingly, mice expressing structural mutants of α1 chains lacking the last two C-terminal laminin globular (LG4–5) domains—which mediate interactions with dystroglycan, heparin, and sufatides—die half a day earlier than the α1-null animals (Schéele et al. 2005). Despite the assembly of embryonic BM, columnar epiblast epithelium and the proamniotic cavity do not form in α1LG4– 5−/− mice, suggesting that the intact α1 chain induces epiblast differentiation via its LG4–5 domains. Because the epiblast is polarized in α1-null mice, these data also indicate that the


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Figure 2 The role of laminins in peri-implantation development. The fully expanded, zona-free blastocyst contains two distinct components: the inner cell mass (ICM) and the trophectoderm shell. Prior to implantation, ICM cells lining the blastocoelic cavity differentiate into hypoblast (or primitive endoderm) cells, which deposit a basement membrane (BM) between them and the remaining undifferentiated ICM. This BM is continuous with the BM deposited by the trophectoderm. After implantation at E4.5, the hypoblast gives rise to two extraembryonic cell lineages: visceral endoderm cells that differentiate from hypoblast cells in contact with the BM and parietal endoderm cells that migrate along the trophectodermal BM. ICM cells adjacent to the BM become polarized and develop into columnar epiblast epithelium (CEE), whereas interior ICM cells undergo apoptosis. By E5.5–E6, the proamniotic cavity forms, and the visceral endoderm and the epiblast (or embryonic ectoderm) are separated by the embryonic BM. Parietal endoderm cells secrete BM components, which incorporate into Reichert’s membrane (RM). During peri-implantation, laminin-111 (α1β1γ1) and laminin-511 (α5β1γ1) are expressed; the consequences of chain-specific gene mutations in mice are described (bottom). 600

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expression of truncated α1 chains may prevent the compensatory upregulation of the α5 chains in embryonic BM. Furthermore, the RM assembles but is fragmented in most α1LG4-5−/− mice, demonstrating that the entire α1 chain is required for full structural stability of RM. After early embryogenesis, BMs express various subsets of laminin isoforms in a tissuespecific manner to fulfill the functional demands of the developing organs. The importance of laminins in BM function during late embryonic and postnatal development has been proven by the analysis of mouse strains with both naturally occurring and targeted mutations in genes encoding laminin subunits (reviewed in Miner & Yurchenco 2004, Yurchenco et al. 2004). For example, laminin α2 deficiency causes severe muscular dystrophy and peripheral nerve defects; the ablation of the gene encoding laminin α3 causes skin blistering; the absence of the α4 chain leads to mild muscular dystrophy and impaired microvessel maturation; and the lack of laminin α5 results in limb, kidney, placental vessel, and neural tube abnormalities as well as defects in interstitial smooth muscle differentiation. Although in some cases compensatory upregulation of other laminin subunits has been reported, this obviously is unable to rescue the phenotype completely. The members of the nidogen family of glycoproteins, nidogen-1 and -2, are ubiquitously expressed components of embryonic BMs with a broad range of binding partners. They are believed to be central organizers of BMs, linking the laminin and collagen networks and incorporating other ECM molecules into the basic scaffold (Yurchenco et al. 2004). Contrary to the putative role of nidogens in BM assembly, both nidogen1- and nidogen-2-null mice (Nid1−/− and Nid2−/− ) are healthy and have no obvious BM defects (Murshed et al. 2000, Schymeinsky et al. 2002), although some BM disruption of brain capillaries accompanied by mild neurological abnormalities was reported in Nid1−/− mice (Dong et al. 2002). Surprisingly, even

Nid1−/− /Nid2−/− double knockouts (Bader et al. 2005) and mice lacking the nidogenbinding site in the laminin γ1 chain (Willem et al. 2002) have BMs, indicating that neither nidogens nor nidogen-laminin interactions per se are critical for BM assembly. However, these mice die shortly after birth from respiratory distress owing to delayed maturation of the lung. Nidogen-1 and nidogen2 double deficiency also results in ultrastructural abnormalities of cardiac BMs, suggesting that nidogens are specifically required for the maintenance of certain BMs and for certain organogenesis processes. The roles of perlecan and agrin. In BMs, the most abundant PG is perlecan, which binds a wide range of molecules, including BM-zone proteins (e.g., laminin, collagen IV, entactin/nidogen, fibulin, collagen XVIII/endostatin), cell surface receptors (e.g., integrins, α-dystroglycan), and growth factors [e.g., fibroblast growth factors (FGFs), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF)] (reviewed in Iozzo 2005). Although this interaction repertoire suggests that perlecan is important for BM assembly, Hspg2−/− mice do develop embryonic BMs. However, deterioration of BMs at regions with increased mechanical stress such as the contracting myocardium leads to tissue damage and bleeding into the pericardial cavity and death of most mutants between E10–E12.5 (Costell et al. 1999). These findings demonstrate that perlecan is dispensable for BM formation but is critically required, like collagen IV, to maintain BM integrity under mechanical force. Interestingly, those Hspg2−/− mice that survive until birth have a reduced number of fibrillin-rich microfibrils at the epidermaldermal junction of the skin, suggesting that perlecan is important for microfibril biogenesis and/or anchoring of these structures to the BM (Tiedemann et al. 2005). At the neuromuscular junctions (NMJs), perlecan is clustered in the postsynaptic BM with a unique set of molecules, including


FGF: fibroblast growth factor VEGF: vascular endothelial growth factor Neuromuscular junction (NMJ): a specialized synapse between the axon terminal of a motor neuron and the effector muscle fiber plasma membrane, where nerve signals are transmitted via neurochemically mediated diffusion to initiate muscle contraction

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acetylcholinesterase (AChE), acetylcholine (ACh) receptors (AChRs), agrin, and dystroglycans (Bezakova & Ruegg 2003). In Hspg2−/− mice, AChE is synthesized but completely excluded from NMJs, indicating that perlecan is essential to localize AChE to the synaptic BM (Arikawa-Hirasawa et al. 2002). This is in agreement with the reduced number of AChE clusters in patients with SchwartzJampel syndrome, a mild chondrodystrophic myotonia disorder caused by perlecan gene mutations generating truncated protein forms (Arikawa-Hirasawa et al. 2002). Mice expressing perlecan that lacks attachment sites for the three HS chains of domain I (Hspg23/3 ) do not show gross defects, implying that these HS chains are not important for the integrity of most BMs and cartilage. However, Hspg23/3 mice have small eyes, and the lenses degenerate within three weeks after birth owing to structural abnormalities of the lens capsule (Rossi et al. 2003). Whereas transgenic experiments indicate a broad range of in vivo functions for perlecan, agrin is mainly known as the crucial player of postsynaptic differentiation at the NMJs. Alternative splicing gives rise to a number of tissue-specific agrins: The so-called z+ -agrin is expressed by neuronal cells and clusters AChRs, whereas the z− -agrin is expressed by nonneuronal cells and inefficiently induces AChR aggregation (reviewed in Bezakova & Ruegg 2003). Mice lacking agrin (agrn−/− ) or z+ -agrin die at birth owing to respiratory distress, display markedly reduced AChR clusters, and fail to form functional postsynaptic structures (Burgess et al. 1999, Gautam et al. 1996). Further genetic studies indicate that agrin is involved in the growth and stabilization of postsynaptic structures but is not required for the initiation of AChR clustering (Lin et al. 2001, Yang et al. 2001). Interestingly, deleting the gene encoding the Ach-synthesizing enzyme choline acetyltransferase (chat−/− ) on an agrin-null background almost completely rescues agrin defects in AChR clustering and NMJ maturation (Misgeld et al. 2005). In vitro ex-


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periments with cultured myoblasts show that ACh functions as an AChR-declustering factor, whereas agrin acts as an antideclustering molecule, protecting the clusters from ACh-induced destabilization. Thus, in vivo, agrin not only plays a role in AChR clustering but is also important in antagonizing the dispersing effect of ACh. The role of agrin outside of NMJs is less well defined. Agrin-deficient embryos show less differentiated interneuronal, sympathetic synapses and defective synaptic transmission in the superior cervical ganglion, implying that neuronal agrin coordinates synaptogenesis throughout the nervous system (Gingras et al. 2002). Recently, the z− -agrin isoform has found a clinically relevant application in amelioration of laminin α2-deficient congenital muscular dystrophy (MDCA1). MDCA1 is a musclewasting disease that often leads to death in early childhood owing to the absence of the BM component laminin-211, which connects muscle BM to the plasma membrane via dystroglycans and integrins. In diseased individuals, laminin-411 is deposited instead; however, it cannot bind dystroglycan. Overexpression of a miniature form of z− -agrin, which can cross-link the laminin α4 chain to dystroglycan, restores BM integrity and improves muscle function in this animal model (Bentzinger et al. 2005, Moll et al. 2001, Qiao et al. 2005).

ECM COMPONENTS AND SIGNALING The knockout mice discussed so far demonstrate how ECM components contribute to the matrix scaffold either as basic structural elements or as organizers/modulators of the structural network. However, the ECM also generates instructive signals to influence cellular behavior by mediating cell-matrix interactions and regulating growth factor availability or presentation. An increasing body of evidence indicates that all classes of matrix molecules are involved in the induction of signaling processes. Below, we summarize

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what we have learned about the significance of ECM-originated signaling in genetically modified mice.


Collagens and Signaling In the past, collagens were viewed solely as structural components of the ECM. Recent analyses of transgenic mice harboring mutant collagen genes provide evidence that this is an oversimplified view. Col6a1−/− mice, for example, demonstrate an unexpected muscle mitochondrial dysfunction (Irwin et al. 2003). Collagen VI–deficient muscles show high levels of spontaneous apoptosis and ultrastructural abnormalities of the sarcoplasmic reticulum and mitochondria. Various stimuli such as oxidative stress or Ca2+ overload can open the high-conductance permeability transition pores (PTPs) in the mitochondrial inner membrane, resulting in mitochondrial depolarization and swelling, which in turn initiate pathways leading to apoptosis and necrosis (Rizzuto 2003). Treatment of the collagen VI– deficient mice with cyclosporin A (CsA) (an immunosuppressive drug which blocks PTP opening) rescued the ultrastructural defects and reduced apoptosis. Therefore, it may be possible to treat collagen VI–related muscle disorders simply with CsA administration. However, the mechanism that connects collagen VI deficiency to mitochondrial abnormalities is still unknown. Because the collagenous domain of collagen VI interacts with cellsurface-receptor integrins, the lack of such an interaction likely affects integrin-dependent cell survival pathways. Collagen XIX is a homotrimeric, rare BMzone collagen with preferential expression in differentiating muscle cells during embryogenesis. The majority of mice lacking collagen XIX (Col19a1N /N ) die before the first month of postnatal life, whereas mice depositing structurally abnormal molecules (Col19a1/ ) survive but have compromised fitness at late adult stages (Sumiyoshi et al. 2004). Both Col19a1−/− and Col19a1/ mice also suffer from a hypertensive lower esophageal

sphincter (LES) due to impaired swallowinginduced, nitric oxide (NO)-dependent relaxation of the SMCs in this region. The BM surrounding the SMCs in mutant animals is abnormal, suggesting that transport of NO from nitrergic nerves to SMCs is critically dependent on a properly organized matrix including collagen XIX. SMC dysfunction and the failure to relax the LES are typical features of patients with achalasia (Goyal 2001), an esophageal motor disorder with largely unknown genetics. The achalasia-like phenotype of the Col19a1-mutant mice raises the possibility that collagen XIX is involved in the etiology of this human disease. In addition, collagen XIX plays an essential role in muscle transdifferentiation of the abdominal segment of the esophagus (Sumiyoshi et al. 2004). In normal mice, the external muscle layer of the esophagus undergoes smooth-toskeletal-muscle conversion in a craniocaudal direction until the third postnatal week of life. This transdifferentiation program is under the control of myogenic regulatory factors (MRFs), such as MyoD or myogenin, that induce the transcription of skeletal muscle– specific genes. In wild-type mice, myogenin expression gradually progresses from the diaphragm level into the abdominal segment of the esophagus, but in Col19a1−/− mice myogenin expression halts at the diaphragm, and as a consequence, transdifferentiation occurs no further. These data implicate collagen XIX in controlling the distribution or activity of ECM signaling molecules that trigger MRF gene expression in the lower part of the esophagus. Alternatively, collagen XIX may modulate cell-matrix or cell-cell interactions that are essential for skeletal myogenesis. The triple-helical structure of native fibrillar collagens binds to and activates the receptor tyrosine kinase DDR2 (discoidin domain receptor 2), which subsequently induces the expression of MMPs (reviewed in Tran et al. 2005). Mice heterozygous for collagen XI mutation (cho/+) develop osteoarthritislike changes in their knee joints (Xu et al. 2003), accompanied by an age-dependent,


DDR2: discoidin domain receptor 2

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coincident induction of DDR2 and MMP-13 expression (Xu et al. 2005). Experiments with cultured normal chondrocytes revealed that the activation of DDR2 by collagen type II leads to the upregulation of MMP-13 (Xu et al. 2005). It is thought that Col11a1 haploinsufficiency alters the distribution of the collagen II/XI fibrillar network in cho/+ mice, resulting in an increased number of interactions between the mutant fibrils and DDR2. The induction of MMP-13 activity by DDR2 signaling consequently increases collagen II degradation in mutant articular cartilage, a hallmark for the progression of osteoarthritis.

Proteoglycans and Growth Factor Signaling PGs can participate in molecular interactions with secreted signaling molecules and cell surface receptors. Among the extracellular HSPGs, perlecan acts as a low-affinity accessory receptor for FGF-2 and promotes FGFdependent cell proliferation and angiogenesis (Aviezer et al. 1994). Providing genetic evidence for the angiogenesis-modulating role of perlecan, Hspg23/3 mice display impaired FGF-2-induced neovascularization, delayed wound healing, and retarded tumor growth (Zhou et al. 2004). These data imply that perlecan regulates FGF-2 signaling and angiogenesis through its HS side chains. Also, disturbed FGF signaling in the growth plate has been suggested to be partially responsible for the chondrocyte proliferation defect in Hspg2−/− mice (Arikawa-Hirasawa et al. 1999). In contrast, perlecan-null embryos show hyperplasia of SMC-specific mesenchymal cells in the cardiac outflow tract, leading to developmental malformations of the great and coronary arteries of the heart (Costell et al. 2002, Gonzalez-Iriarte et al. 2003). Perlecan inhibits SMC proliferation through the tumor suppressor PTEN, a phosphatase that negatively regulates Akt (protein kinase B) and focal adhesion kinase signaling (Garl et al. 2004). How perlecan influ604

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ences PTEN activity is unknown, but interactions between the core protein and cell surface receptors regulating PTEN activity have been suggested. Alternatively, the HS chains of perlecan may sequester growth factors, thus decreasing growth factor–mediated SMC proliferation. In support of this hypothesis, Hspg23/3 mice show increased SMC growth and intimal hyperplasia after carotid artery injury (Tran et al. 2004). Knockout mouse models provide evidence for the role of SLRPs in growth factor signaling and direct cell growth regulation. At least three SLRPs (decorin, fibromodulin, and biglycan) interact with TGF-β, a cytokine involved in cellular processes such as proliferation, survival, and differentiation (Ameye & Young 2002). In biglycan-null and biglycan/decorin double-knockout mice, the observed osteopenia is associated with increased apoptosis of bone marrow stromal cells (BMSCs), resulting in decreased capacity of BMSCs to form colonies in vitro (Bi et al. 2005, Chen et al. 2002). This suggests that the reduced number of osteoprogenitor cells is partially responsible for the bone defect in these mice. The simultaneous lack of biglycan and decorin in the stromal matrix results in increased access to TGF-β1, leading to overactivation of TGF-β1-mediated signaling pathways (Bi et al. 2005). Biglycan/decorindeficient BMSCs show significantly higher phosphorylation of the TGF-β-responsive downstream signaling molecules Smad2 and Smad3 as well as increased activity of the key apoptotic protease caspase-3. The activity of Smad1, which mediates signals from other members of the TGF-β superfamily such as BMP2 and BMP4, is also increased in doublemutant cells. Because the differentiation capacity of mutant BMSCs is normal, these data suggest that biglycan and decorin cooperate to modulate the balance between growth and apoptosis of BMSCs by controlling the amount of sequestered and free TGF-β in the bone marrow matrix. Conversely, when only biglycan is absent, differentiation of calvarial preosteoblasts to mature osteoblasts is


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impaired owing to reduced BMP4-mediated signaling (Chen et al. 2004). In a proposed model, decorin and biglycan may competitively bind BMPs/TGF-β to sequester them in the matrix or present them to cellular receptors, respectively. Thus, the absence of biglycan in the presence of decorin traps these growth factors in a matrix compartment, reducing the amount of available BMPs. In the absence of both biglycan and decorin, BMSCs have unrestricted access to growth factors. Taken together, these experiments demonstrate that decorin and biglycan play an important role in defining a permissive microenvironment for osteoblast differentiation and survival. Other studies on decorin- and lumicandeficient mice further strengthen the view that SLRPs are important mediators of cell proliferation and survival. In accordance with findings demonstrating that ectopic expression of decorin in fibroblasts, malignant cell lines, and tumor xenografts suppresses growth (Ameye & Young 2002, Reed & Iozzo 2002), decorin deficiency induces fibroblast proliferation in periodontal ligaments (Hakkinen et al. 2000) and accelerates lymphoma tumorigenesis in mice lacking the tumor suppressor gene p53 (Iozzo et al. 1999). On the other hand, the absence of decorin in an obstructed nephropathy animal model resulted in increased apoptosis of tubular epithelial cells associated with lower levels of p27KIP1 and enhanced TGF-β1 expression, providing direct evidence for the protective role of decorin in fibrotic kidney disease via both TGF-β-dependent and -independent mechanisms (Schaefer et al. 2002). In the cornea, lumican regulates proliferation and apoptosis of stromal keratocytes during wound healing (Vij et al. 2004). Lumican-null mice show increased proliferation of these cells caused by downregulating the cell cycle control protein p53 and its downstream target p21WAF1/CIP1 . Apoptosis is also decreased in the mutant cornea by negative regulation of the Fas/Fas ligand pathway. Lumican may influence this pathway either by interacting with Fas and

thereby modulating the amount of Fas on the cell surface or by binding the soluble Fas ligand and presenting it to Fas.

Microfibrils and Growth Factor Signaling There is an increasing amount of genetic evidence that fibrillin-rich microfibrils play important roles in TGF-β/BMP signaling (reviewed in Judge & Dietz 2005, Kielty et al. 2002, Ramirez et al. 2004). TGF-βs are secreted in a latent form in a complex that includes LTBP-1, -3, or -4. These latent complexes are sequestered in the ECM; upon activation, TGF-β is released and initiates downstream signaling cascades by interacting with cell surface receptors (Annes et al. 2003). The structural homology between fibrillins and LTBPs and the capability of LTBPs to bind fibrillins led to the hypothesis that microfibrils play a role in TGF-β signaling. Indeed, hypomorphic fibrillin-1 mice develop Marfan-like emphysema and mitral valve prolapse associated with increased TGF-β activation (Neptune et al. 2003, Ng et al. 2004). Both the lung and heart phenotypes can be rescued by administration of TGF-β-neutralizing antibodies, suggesting that fibrillin-1-LTBP interactions are important for latent complex sequestration and TGF-β immobilization. Ltbp-3−/− and hypomorphic Ltbp-4 mice also develop emphysema, which is apparently associated with decreased TGF-β signaling (Colarossi et al. 2005, Sterner-Kock et al. 2002). Interestingly, LTBP-4 deficiency specifically blocks TGFβ1 secretion and activation, which is accompanied by an increased amount of BMP4 and enhanced expression of BMP4 target genes (Koli et al. 2004). This finding implies that the lung phenotype is partially due to a switch from TGF-β to BMP4 signaling. Taken together, these mouse models suggest that fibrillin-1 and LTBPs tightly control growth factor levels during lung development and that deviations from the usual physiological TGF-β concentration may have the same pathological


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consequence whether concentration increases or decreases. Additional support for the role of fibrillins/LTBPs in the modulation of growth factor signaling is provided by the analyses of the Fbn2 and Ltbp-3 knockout mice. Ltbp-3-null mice develop bone abnormalities, including cranio-facial malformations, osteoarthritis, and osteopetrosis, as a result of decreased TGF-β signaling (Dabovic et al. 2002, 2005). Fibrillin-2-deficient mice display bilateral syndactyly, associated with impaired mesenchyme differentiation, probably owing to the lack of functional interactions between the disorganized, fibrillin-2-deficient microfibrils and growth factors (Arteaga-Solis et al. 2001). Mice double heterozygous for Fbn2 and Bmp-7 exhibit syndactyly and polydactyly (the characteristic phenotype of the corresponding single-homozygous mutants, respectively), demonstrating that perturbed BMP-7 signaling may be at least partially causative for syndactyly in Fbn2−/− mice (Arteaga-Solis et al. 2001).


Shh: sonic hedgehog

Laminins in Signaling Binding of laminin to integrin and nonintegrin cell surface receptors triggers multiple signal transduction pathways modulating cellular behavior in both physiological and pathological processes. A vast amount of in vitro data implicates laminin-induced signaling in cell differentiation, migration, and proliferation; in the regulation of gene expression; and in tumor progression and angiogenesis (Ekblom et al. 2003, GivantHorwitz et al. 2005). Less is known about laminin signaling in vivo, but recent experiments in mice highlight some details of hair and peripheral nerve development. Laminin-511 is the major laminin in the BM below the elongating hair germ epithelium. The developing skin in the late embryonic lethal α5 chain–deficient mice contains significantly fewer hair germs than does control skin, and α5-null skin grafts do not develop hairs on nude mice (Li et al. 2003). 606

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The administration of antibodies to human laminin-511 results in a similar block of hair growth in human scalp skin grafts. Subsequent studies demonstrated that the failure of hair germ elongation in α5-mutant grafts is accompanied by the loss of hair follicle– associated cellular proliferation and of sonic hedgehog (Shh) signaling (Li et al. 2003). Shh is a critical morphogen for proliferation during hair development; Shh-null mice show impaired germ elongation (Chiang et al. 1999). Laminin α5–deficient embryonic skin and graft samples do not express Shh or its target gene Gli1 (Li et al. 2003), demonstrating that laminin-511 is required for Shh-driven hair follicle morphogenesis, likely through binding to integrins because loss of α3 or β1 integrin leads to similar hair follicle defects (Brakebusch et al. 2000, Conti et al. 2003). Much evidence suggests that laminin-rich BMs synthesized by Schwann cells play a critical role in axon myelination during peripheral nerve development (Miner & Yurchenco 2004). Mice and humans lacking the laminin α2 chain and mice with a Schwann cell– specific mutation in the gene encoding the γ1 chain all display dysmyelinating peripheral neuropathy. The elimination of the γ1 chain in Schwann cells results in the depletion of all laminin isoforms, which consequently impairs axon–Schwann cell interactions and arrests Schwann cells in the promyelinating stage owing to a failure to downregulate the differentiation-promoting transcription factor Oct-6 (Yu et al. 2005). The lack of proper interactions between axons and Schwann cells reduces phosphorylation of the β-neuregulin1 receptors ErbB1 and ErbB3, resulting in decreased Schwann cell proliferation. At postnatal stages, mutant Schwann cells display impaired PI3-kinase/Akt-driven signaling, leading to the activation of proapoptotic caspase cascade. Because the injection of laminin peptide into mutant sciatic nerves partially rescues apoptosis, laminin-induced signals obviously participate in the regulation of Schwann cell survival.

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Fibronectin Fibronectins (Fns) are large, adhesive glycoproteins that exist in two forms: as soluble plasma Fn (pFn) in the blood and as insoluble cellular Fn (cFn) in the ECM. Fn influences cellular activities and matrix organization by interacting with integrins, syndecans, and ECM molecules. Mice lacking all Fn isoforms die at E8.5 from severe defects in cell migration and mesoderm formation (George et al. 1993), demonstrating the crucial role of Fns during mid-embryogenesis. Interestingly, conditional knockout mice lacking pFn (Sakai et al. 2001) or cFn in chon´ et al. 2003) appear normal, drocytes (Aszodi indicating that these isoforms are apparently dispensable for hemostasis and cartilage development, respectively. However, pFn contributes to some repair processes. In a mouse model of arterial injury, pFn deficiency reduces thrombus growth and stability under shear stress owing to impaired pFn-mediated cohesion among platelets (Ni et al. 2003). Following cerebral ischemia, the absence of pFn results in increased infarct size, which is associated with an elevated level of apoptosis in both neuronal and nonneuronal cells (Sakai et al. 2001). Loss of interaction between pFn and α5β1 integrin results in reduced expression of the antiapoptotic protein Bcl-2 and in the activation of the apoptosis effector caspase-3. Thus, pFn supports cell survival at brain injury sites through integrin-mediated signals.

COLLAGEN-DERIVED MATRICRYPTINS AND ANGIOGENESIS In recent years, there has been increasing evidence that distinct domains within ECM proteins can signal through cell surface receptors and regulate biological functions. These so-called matrikine subdomains either act directly from native ECM macromolecules (natural matrikines) or must first be exposed by a conformational change or proteolytic

processing (cryptic matrikines) (Tran et al. 2005). In the past decade, most attention has focused on cryptic fragments generated from the NC1 domain of collagen IV α1/α2/α3 chains (termed arresten, canstatin, and tumstatin, respectively), collagen XV (restin), and collagen XVIII (endostatin) (Figure 3a) (Iozzo 2005). These blood-circulating fragments inhibit angiogenesis in both in vitro and in vivo assays and reduce tumor growth in animal models (Marneros & Olsen 2001). Surprisingly, mice lacking the α3 chain of collagen IV (Hamano et al. 2003), collagen XV (Eklund et al. 2001), collagen XVIII (Fukai et al. 2002), or both collagens XV and XVIII (Ylikarppa et al. 2003) do not show overt defects in physiological angiogenesis, suggesting that cleaved NC1 fragments are not essential components of angiogenesis-regulating pathways. Nevertheless, more detailed analyses reveal that their function may be restricted to certain tissues and/or relevant under certain pathological conditions. Mice lacking the tumstatin-producing α3 chain of collagen IV show increased tumor growth and tumor-associated angiogenesis as compared with wild-type mice (Hamano et al. 2003). Administration of physiological concentrations of tumstatin to null mice decreased both the number of blood vessels and the rate of tumor growth to wildtype levels, formally confirming that the tumstatin domain alone is an endogenous suppressor of pathological angiogenesis. Tumstatin is cleaved from the α3(IV) chain by BM-degrading MMPs (Hamano et al. 2003). MMP-9-deficient mice have decreased circulating tumstatin levels and show accelerated tumor growth, which can be reverted to wild-type levels by raising tumstatin to a normal physiological concentration by exogenous administration (Hamano et al. 2003). Thus, MMPs, which are generally thought of as positive regulators of tumor angiogenesis, can serve an opposing function by liberating endogenous antiangiogenic fragments such as tumstatin (Hamano & Kalluri 2005).


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Col18a1-null mice display defects in posterior eye vasculature development (reviewed in Marneros & Olsen 2005), indicating a role for collagen XVIII/endostatin in influencing

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the vascularization of specific anatomical locations. The abnormalities manifest postnatally and include the delayed regression of hyaloid vessels along the surface of the retina as well


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as impaired outgrowth and patterning of the retinal vasculature. Interestingly, the defects are accompanied by reduced neuroglial expression of VEGF (Fukai et al. 2002), which is normally upregulated by hypoxia at the onset of hyaloid vessel regression and stimulates vascular outgrowth from the optic-nerve head. The mechanism behind delayed vessel regression in the Col18a1-null mice is not clear, but experiments with aortic explants and lung endothelial cells isolated from wild-type and mutant mice (Li & Olsen 2004) may provide some clues. This model is characterized by a dynamic process of microvessel elongation and regression in aortic explants under serum-free medium conditions. The mutant explants showed increased vessel outgrowth, which was reversed by the addition of physiological levels of endostatin to the cultures. Furthermore, isolated lung endothelial cells from Col18a1-null mice exhibited increased adhesion to fibronectin as compared with wild-type cells. Because proliferation and migration of mutant endothelial cells were normal, according to these findings the increased adherence of endothelial cells to the FNcontaining matrix stabilizes newly formed ves-

sels and reduces regression, resulting in a net increase of microvessel outgrowth. Thus, collagen XVIII/endostatin may exert an antiangiogenic effect via modulating interactions between endothelial cells and the underlying ECM of vascular basement membranes. In vitro studies show that human endostatin and arresten interact with α5β1 and α1β1 integrins, respectively, and inhibit EC migration by blocking the FAK/Ras/Raf/ ERK1/p38 mitogen–activated protein kinase pathway (Sudhakar et al. 2005, Sudhakar et al. 2003). Endostatin also induces the disassembly of the actin cytoskeleton via ¨ downregulation of RhoA activity (Wickstrom et al. 2003). Tumstatin interacts with αvβ3 integrin, leading to the inhibition of the FAK/PI3K/Akt/mTOR-mediated protein synthesis pathway (Figure 3b) (Maeshima et al. 2002, Sudhakar et al. 2003). In agreement with the in vitro findings, endostatin but not tumstatin inhibits neovascularization in Matrigel plugs implanted into β3 integrin–deficient mice (Hamano et al. 2003), and arresten fails to inhibit angiogenesis and tumor growth in mice lacking the α1 integrin subunit (Sudhakar et al. 2005). Therefore,

←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− Figure 3 Collagen-derived antiangiogenic fragments. (a) Partial structure of collagen IV, collagen XV, and collagen XVIII trimers. In each collagen the triple-helical motifs are connected to C-terminal noncollagenous (NC)-1 domains containing a trimerization domain in collagens XV and XVIII (squares), a protease-sensitive hinge region, and a globular domain. For illustrative purposes, collagen IV is represented as a heterotrimer of α1(IV)α2(IV)α3(IV). Following proteolytic cleavage (small arrows), the NC1 domains liberate globular antiangiogenic fragments termed arresten (ar) [yellow oval; from α1(IV) chain], canstatin (cs) [blue oval; from α2(IV) chain], tumstatin (ts) [ pink oval; from α3(IV) chain], restin (re) [white ovals; from α1(XV) chains], and endostatin (es) [green ovals; from α1(XVIII) chains]. (b) Regulation of integrin-mediated signaling cascades by tumstatin (ts), arresten (ar), and endostatin (es). Tumstatin and arresten interact with αvβ3 and α1β1 integrins, respectively, whereas endostatin interacts, perhaps simultaneously or subsequently, with α5β1 integrin, cell surface HSPG, and caveolin-1 (cav1). All fragments inhibit focal adhesion kinase (FAK) activation. Arresten and endostatin subsequently inhibit downstream cascades ( yellow/green ovals) involving extracellular signal–regulated kinase 1 (ERK1) and p38 mitogen–activated protein kinase (p38) and impair cell migration (in the case of endostatin) or cell migration and proliferation (in the case of arresten). In contrast, tumstatin decreases cell proliferation by inhibiting the signaling pathway ( pink ovals) that includes phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR). This prevents the dissociation of eukaryotic initiation factor 4E protein (eIF4E) from 4E-binding protein 1 (4EBP1) and inhibits protein synthesis. Endostatin also inhibits RhoA function ( green ovals) independently of FAK by the stimulation of caveolin-associated Src, which in turn activates p190 RhoGAP, leading to RhoA inactivation, actin disassembly, and inhibition of cell migration and adhesion. www.annualreviews.org • ECM, Mouse Genetics, Structure, Signaling

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there is good evidence that bioactive NC1 fragments exert their antiangiogenic effects via modulation of integrin-dependent signaling pathways. Furthermore, recent studies show that the antiangiogenic function of these substances may depend on plasma adhesion proteins. For example, endostatin and anastellin (an antiangiogenic fragment derived from fibronectin) do not inhibit Matrigel plug vascularization in mice lacking pFn (Yi et al. 2003). In an emerging model, pFn serves as a cofactor that delivers angiostatic fragments to the sites of angiogenesis and presents them to integrin receptors (Akerman et al. 2005).


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MATRICELLULAR PROTEINS The term matricellular proteins is applied to certain members of several ECM protein families, which primarily modulate cellular functions and have no obvious structural role in the matrix. The diverse group of matricellular proteins currently includes thrombospondin (TSP) 1 and 2, SPARC (also known as osteonectin or BM-40), SC1/hevin, tenascin C and X, osteopontin, and the members of the CCN (cyr61, ctgf, nov) protein family. Matricellular proteins share some common features. For example, (a) they show high expression levels during embryogenesis, declining postnatally; (b) they bind to cell surface receptors, growth factors, cytokines, and proteases; (c) they mediate de-adhesion of anchoragedependent cells; and (d ) their elimination from the matrix is usually not incompatible with life (Bornstein & Sage 2002, Bornstein et al. 2004). TSP1 and TSP2 are heterotrimeric molecules forming a distinct subgroup within the thrombospondin family. Both TSP1 and TSP2 are potent angiogenesis inhibitors in vitro, and in mice their deficiency increases vascular density in skin [TSP1 (Crawford et al. 1998)] or in multiple tissues [TSP2 (Kyriakides et al. 1998)]. In the eye, TSP1 and TSP2 direct inflammation-induced corneal and developmental iris angiogenesis, respec610

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tively (Cursiefen et al. 2004). TSP1- and TSP2-null mice display increased tumorigenesis (Hawighorst et al. 2001, RodriguezManzaneque et al. 2001), whereas overexpressing TSP1 in mammary tumor–prone mice reduces tumor incidence (RodriguezManzaneque et al. 2001). Furthermore, TSP1/TSP2 have distinct roles during wound healing: The lack of TSP1 or both TSP1 and TSP2 impairs the early phase of the wound response, leading to delayed healing, whereas TSP2-null wounds show increased neovascularization and accelerated healing rate (Agah et al. 2002). Collectively, these data indicate that TSP1 and TSP2 are indeed angiogenic regulators in vivo. The phenotypes of other matricellular knockout mice show similarities. Enhanced tumor growth and accelerated wound closure have been reported in SPARC-null mice (Bradshaw et al. 2002, Brekken et al. 2003), and tenascin-X knockouts show increased tumor invasion (Matsumoto et al. 2001). Tenascin-X deficiency causes reduced collagen I content in the skin, leading to skin hyperextensibility and mimicking the mutation in the human TNXB gene that causes EhlersDanlos syndrome (Mao et al. 2002). A reduction in collagen I has been reported in the dermis and fat pads of SPARC-null mice, resulting in impaired tensile strength of the skin and adiposity, respectively (Bradshaw et al. 2003). TSP2 knockout mice also have fragile skin associated with disorganized dermal collagen architecture (Kyriakides et al. 1998). In addition, many matricellular proteins are expressed in the skeleton, and the corresponding knockout mice display skeletal abnormalities during bone development and regeneration (Alford & Hankenson 2006). Although the mechanistic details underlying the defects are not clear, several lines of evidence suggest that matricellular proteins exert their biological functions via the regulation of growth factor and protease activities, which in turn affect cell proliferation/ survival and ECM deposition. For example, TSP1 binds and activates latent TGF-β1


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in vitro (Annes et al. 2003, Hyytiainen et al. 2004). In vivo, TSP1- and TGF-β1-null mice display an overlapping phenotype (e.g., in the lung and pancreas), and the defects of the TSP1 knockout mice can be partially restored with a TGF-β1-activating peptide derived from TSP1, supporting the view that TSP1 is an in vivo activator of latent TGFβ1 (Crawford et al. 1998). In contrast, SPARC interacts with the TGF-β1-receptor complex in the presence of TGF-β1, which in turn modulates the activation of downstream signaling cascades (Francki et al. 2004). There is also a growing body of evidence suggesting that matricellular proteins can control the expression levels of MMPs (Bornstein et al. 2004). TSP2-null tissues show elevated MMP-2 levels, leading to MMP-2-induced proteolysis of tissue transglutaminase, an enzyme involved in ECM stabilization, thus providing a feasible explanation for the matrix abnormalities observed in TSP2-deficient skin (Agah et al. 2005). Similarly, levels of MMP2 (and MMP-9) were increased in malignant gliomas propagated in TSP2-null mice (Fears et al. 2005). According to a current model, TSP2 controls MMP-2 levels by promoting low-density lipoprotein receptor–related protein (LRP)-mediated endocytosis of MMP2. In contrast, TSP1 suppresses the processing of pro-MMP-9 by MMP-3; therefore, the absence of TSP1 results in increased levels of active MMP-9 during tumorigenesis, facilitating both angiogenesis and tumor invasion (Rodriguez-Manzaneque et al. 2001). The enhanced metastasis in tenascin-X-null mice is associated with increased MMP-2 and MMP-9 activities (Matsumoto et al. 2001). The role of matricellular proteins in central nervous system (CNS) development recently was identified through knockout experiments. TSP1/TSP2 are secreted by astrocytes and promote synaptogenesis both in vivo and in vitro (Christopherson et al. 2005). These two molecules are present in the murine CNS when synapses are established, and the brains of TSP1/TSP2 doublenull mice develop approximately 40% fewer

synapses than the brains of wild-type mice. TSPs probably act in concert with other astrocyte-derived signals to produce functional CNS synapses (Christopherson et al. 2005). Mice lacking SC1/hevin have no overt phenotype. The cerebral cortex of these animals, however, displays neuronal misplacement, suggesting that SC1 is important for neuronal migration in the developing cortex via its antiadhesive activity (Gongidi et al. 2004). Lastly, the ablation of tenascin-C or tenascin-R (which may also be a matricellular protein) leads to various neuronal dysfunctions (Evers et al. 2002, Saghatelyan et al. 2004). Among the matricellular proteins, two members of the CCN family, CCN1 and CCN2, seem to be essential for life. Disruption of CCN1 (CYR61) causes prenatal lethality owing to impaired placental and embryonic vascular development (Mo et al. 2002). CCN2 [or CTGF (connective tissue growth factor)]-null mice die at birth and develop skeletal abnormalities such as defective matrix remodeling and angiogenesis in the growth plate (Ivkovic et al. 2003). The high apoptotic rate of the vascular cells in the Ccn1−/− mice and the decreased proliferation rate of Ccn2−/− chondrocytes imply that a general function of CCN proteins is to control cell death and survival in a context-dependent manner. Indeed, cell culture experiments indicate that CCN1 induces apoptosis in fibroblasts, whereas it promotes the survival of endothelial cells (Todorovic et al. 2005).

CONCLUDING REMARKS The molecular constituents of the ECM form larger complexes that provide structural and instructive signals for tissue differentiation, development, and function. The composition of the ECM and the distribution of its components define tissue architecture and cellular responses for cytokine/growth factor stimulation. The complexity of the ECM makes it difficult to identify the functional repertoire of ECM proteins by biochemical or cell culture


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experiments. Hence, mouse models are particularly useful for analyzing the biological significance of ECM components in a wide variety of in vivo processes. Mouse strains with engineered mutations in genes encoding ECM proteins have shown that most ECM components have roles beyond a simple structural scaffold and have sometimes revealed unexpected functions that cannot be predicted by in vitro approaches. Knockout mice and cell lines established from them have helped

to elucidate intracellular signal transduction cascades activated by ECM-cell interactions. In the future, the analysis of mice carrying null mutations in ECM molecules, in combination with knock-in approaches to address specific mutations, will enable us to identify the mechanisms driving a wide variety of pathologies. The involvement of ECM in regulating and maintaining tissue homeostasis will suggest novel therapies with which to combat diseases with an abnormal ECM component.

SUMMARY POINTS 1. Extracellular matrix proteins are modular, multifunctional molecules that provide a structural as well as an instructive environment for cells and tissues. 2. Genetically modified mice provide an excellent in vivo approach with which to discover the functions of ECM proteins for developmental, physiological, and pathological processes. 3. The mechanical stability of connective tissues and basement membranes is determined by the proper assembly of ECM proteins into interactive macromolecular architectures. 4. ECM components integrate growth factor– and integrin-mediated signaling pathways by controlling the presentation of growth factors to cells as well as by binding directly to cell surface receptors such as integrins. 5. The antiangiogenic role of collagen-derived matrikines is context dependent and involves integrin-mediated signaling cascades. 6. Matricellular proteins modulate cell functions primarily by regulating growth factor and MMP activities.

ACKNOWLEDGMENTS K.L. is supported by a Marie Curie International Fellowship within the 6th European Community Framework Programme. A.A. and R.F. are supported by the Deutsche Forschungsgemeinschaft, the Max Planck Society, and the Fonds der Chemischen Industrie. The authors apologize to those whose work has not been cited owing to space limitations.

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Shows that collagen VI deficiency induces mitochondrial pathogenesis that can be fully reverted by cyclosporin A treatment.

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Demonstrates that laminin-10 controls hair follicle development via modulating Shh expression.

This study, together with Smyth et al. (1999), clarifies the functional role of individual laminin chains in peri-implantation mouse embryos.

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Demonstrates the antagonistic effects of acetylcholine and agrin on postsynaptic differentiation using gene-targeted mice.

Shows that fibrillin-1deficiency leads to increased TGF-β activation, providing an explanation for the development of emphysema in Marfan sydrome.

Shows that collagen IV is not important for the formation of BMs but is required for their structural integrity.

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Demonstrates the dual, structural, and instructive roles of collagen XIX in esophageal development.

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Todorovic V, Chen CC, Hay N, Lau LF. 2005. The matrix protein CCN1(CYR61) induces apoptosis in fibroblasts. J. Cell Biol. 171:559–68 Tran KT, Lamb P, Deng JS. 2005. Matrikines and matricryptins: implications for cutaneous cancers and skin repair. J. Dermatol. Sci. 40:11–20 Tran PK, Tran-Lundmark K, Soininen R, Tryggvason K, Thyberg J, Hedin U. 2004. Increased intimal hyperplasia and smooth muscle cell proliferation in transgenic mice with heparan sulfate-deficient perlecan. Circ. Res. 94:550–58 Utriainen A, Sormunen R, Kettunen M, Carvalhaes LS, Sajanti E, et al. 2004. Structurally altered basement membranes and hydrocephalus in a type XVIII collagen deficient mouse line. Hum. Mol. Genet. 13:2089–99 Vij N, Roberts L, Joyce S, Chakravarti S. 2004. Lumican suppresses cell proliferation and aids Fas-Fas ligand mediated apoptosis: implications in the cornea. Exp. Eye Res. 78:957–71 Waddington RJ, Roberts HC, Sugars RV, Schonherr E. 2003. Differential roles for small leucine-rich proteoglycans in bone formation. Eur. Cell. Mater. 6:12–21 Wai AWK, Ng LJ, Watanabe H, Yamada Y, Tam PPL, Cheah KSE. 1998. Disrupted expression of matrix genes in the growth plate of the mouse cartilage matrix deficiency (cmd) mutant. Dev. Genet. 22:349–58 Watanabe H, Kimata K, Line S, Strong D, Gao Y, et al. 1994. Mouse cartilage matrix deficiency (cmd) caused by a 7 bp deletion in the aggrecan gene. Nat. Genet. 7:154–57 This paper, together with Chanut-Delalande et al. (2004), provides new insight into the process of collagen fibrillogenesis.

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Zanetti M, Braghetta P, Sabatelli P, Mura I, Doliana R, et al. 2004. EMILIN-1 deficiency induces elastogenesis and vascular cell defects. Mol. Cell. Biol. 24:638–50 Zhou XH, Brakebusch C, Matthies H, Oohashi T, Hirsch E, et al. 2001. Neurocan is dispensable for brain development. Mol. Cell. Biol. 21:5970–78 Zhou Z, Wang J, Cao R, Morita H, Soininen R, et al. 2004. Impaired angiogenesis, delayed wound healing and retarded tumor growth in perlecan heparan sulfate-deficient mice. Cancer Res. 64:4699–702


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Aszódi, Legate, Nakchbandi, and Fässler

Supplementary Table 1. Gene Targeting and Naturally Occuring Mutations in Secreted ECM Proteins Protein/Gene Aggrecana Agrin Biglycan Brevican CCN1/CYR61 CCN2/CTGF Collagen I, α1 Collagen I, α2a Collagen II, α1 Collagen III, α1 Collagen IV, α1/α2 Collagen IV, α3 Collagen V, α1 Collagen V, α2 Collagen VI, α1 Collagen VII, α1 Collagen VIII, α1 Collagen IX, α1 Collagen X, α1 Collagen XI, α1a Collagen XI, α2 Collagen XV, α1 Collagen XVIII, α1 Collagen XIX, α1 COMP Decorin Elastin Emilin-1 Fibrillin-1 Fibrillin-2 Fibronectin Plasma Fibronectin Fibromodulin Fibulin-1 Fibulin-5 Hevin/SC1 Keratocan Laminin α1 Laminin α2 Laminin α3 Laminin α4

Phenotype

References

L, severe chondrodyspasia, cleft palate Wai et al. 1998, Watanabe et al. 1994 L, neuromuscular abnormalities Gautam et al. 1996, Burgess et al. 1999 V, osteoporosis, osteoarthritis, tendon ossification Xu et al. 1998, Ameye et al. 2002 collagen fibril abnormalities, osteoblast defects Corsi et al. 2002, Chen et al. 2002, 2004 V, mild defect in hyppocampal long-term potentiation Brakebusch et al. 2002 EL, placental and embryonic vascular defects Mo et al. 2002 L, defects in endochondral bone formation Ivkovic et al. 2003 EL, rupture of blood vessels Lohler et al. 1984 V, bone fracture, osteopenia Chipman et al. 1993 L, severe chondrodysplasia, intervertebral disc defect S-W Li et al. 1995, Aszodi et al. 1998 L, cardiovascular and skin defects Liu et al. 1997 EL, basement membrane defects Pöschl et al. 2004 L, renal failure, gromeluronephritis Cosgrove et al. 1996, Miner & Sanes 1996 EL, cardiovascular failure, lack of collagen fibrils Chanut-Delalande et al. 2004 L,skin fragility, corneal and skeletal defects Andrikopoulos et al. 1995, Wenstrup et al. 2004 V, early onset myopthy, mitochondrial dysfunction Bonaldo et al. 1998, Irwin et al. 2003 L, severe subepidermal blistering Heinonen et al. 1999 V, anterior segment dysgenesis Hopfer et al. 2005 V, early-onset osteoarthritis, hearing loss Fässler et al. 1994, Asamura et al. 2005 V, mild chondrodysplasia Kwan et al. 1997 L, severe chondrodysplasia Y Li et al. 1995 V, moderate chondrodysplasia, hearing loss Li et al. 2001 V, skeletal myopathy, cardiovascular defects Eklund et al. 2001 V, eye abnormalities Fukai et al. 2002, Marneros & Olsen 2003 Marneros et al. 2004, Ylikarppa et al 2003 susceptibility to hydrocephalus Ultriainen et al. 2004 V, esophagus abnormalities Sumiyoshi et al. 2004 V, no obvious phenotype Svensson et al. 2002 V, skin fragility, type I collagen fibril abnormalities Danielson et al. 1997, Corsi et al. 2002 L, obstructive arterial disease Li et al. 1998 V, mild abnormalities in skin and aorta Zanetti et al. 2004 L, early-onset vascular abnormalities Carta et al. 2006 V, limb-patterning defect Arteaga-Solis et al. 2001 EL, neural tube, mesodermal and vascular defects George et al. 1993 V, defects in brain and arterial repair processes Sakai et al. 2001, Ni et al. 2003 V, abnormal tendons, osteoarthritis Svensson et al. 1999, Ameye at al. 2002 L, hemorrhages, lung and kidney defects Kostka et al. 2001 V, elastic fiber, lung, skin and vascular defects Nakamura et al. 2002, Yanagisawa et al. 2002 V, cortical neuron misplacement Gongidi et al. 2004 V, thin cornea with abnormal collagen fibril spacing Liu et al. 2003 EL, lack of Reichert´s membrane Miner et al. 2004 L, muscular dystrophy, peripheral neuropathy Miyagoe et al. 1997 L, skin blistering Ryan et al. 1999 V, microvascular and NMJ defects Patton et al. 2001, Thyboll et al. 2002

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Supplemental Material: Annu. Rev. Cell. Dev. Biol. 2006. 22:591-621 doi: 10.1146/annurev.cellbio.22.010305.104258 What Mouse Mutants Teach Us About Extracellular Matrix Function

Aszódi, Legate, Nakchbandi, and Fässler

Table 1. (Continued) Protein/Gene Laminin α5 Laminin β1 Laminin β2 Laminin γ1 Laminin γ2 Link protein LTBP-2 LTBP-3 LTBP-4b Lubricin Lumican Matrilin-1 Matrilin-2 Matrilin-3 Matrix-Gla protein Mimecan Netrin-1b Neurocan Nidogen-1 Nidogen-2 Osteocalcin Osteopontin Perlecan SPARC Tenascin-C Tenascin-R Tenascin-X Thrombospondin-1 Thrombospondin-2 Thrombospondin-3 Versicana Vitronectin

Phenotype

References

EL, kidney, limb, neural tube and placental defects, defect in hair morphogenesis EL, failure of basement membranes formation L, neuromuscular, renal and CNS defects

Miner et al. 1998, Miner & Li 2000 Li et al. 2003 Miner et al. 2004 Libby et al. 1999; Noakes et al. 1995a,b; Patton et al. 1997 EL, failure of basement mebranes formation Smyth et al. 1999 L, skin blistering Meng et al. 2003 L, skeletal abnormalities Watanabe & Yamada 1999 EL, lethality between E3-E6 due to unknown reason Shipley et al. 2000 V, skeletal abnormalities, lung emhysema Dabovic et al. 2002, Colarossi et al. 2005 V, abnormal elastic fibers, lung and colon defects Sterner-Kock et al. 2002 V, articular joint defects Rhee et al. 2005 V, corneal opacity, skin fragility Chakravarti et al. 1998, 2000 V, no obvious phenotype, thicker fibrils in cartilage Aszodi et al. 1999, Huang et al. 1999 V, no obvious phenotype Mátés et al. 2004 V, no obvious phenotype Ko et al. 2004 V, abnormal calcification in cartilage and arteries Luo et al. 1997 V, skin fragility, collagen abnormalities Tasheva et al. 2002 V, defective axon guidance and abnormal Serafini et al. 1996 mammary gland morphogenesis Srinivasan et al. 2003 V, mild defect in hyppocampal long-term potentiation Zhou et al. 2001 V, no obvious phenotype Murshed et al. 2000 V, no overt phenotype, mild neurological defects Dong et al. 2002, Schymeinsky et al. 2002 V, increased bone formation Ducy et al. 1996 V, impaired wound healing Liaw et al. 1998 EL-L, basement membrane and skeletal defects, Arikawa-Hirasawa et al. 1999, Costell et al. 1999 reduced number of microfibrils in skin Tiedemann et al. 2005 V, late-onset cataract, increased adiposity, Gilmour et al. 1998, Bradshaw et al. 2003 osteopenia Delany et al. 2000 V, grossly normal, mild behavioral and hematopoietic Forsberg et al. 1996, Fukamauchi et al. 1996, defects, subtle wound healing abnormalities Evers et al. 2002, Matsuda et al. 1999 V, behavioral abnormalities Freitag et al. 2003, Montag-Sallaz & Montag 2003 olfactory bulb defects Saghatelyan et al. 2004 V, increased tumor growth, skin hyperextensibility Matsumoto et al. 2001, Mao et al. 2002 V, spinal lordosis, lung, pancreas, hematopoietic Agah et al. 2002, Crawford et al. 1998, and skin vascular defects, delayed wound healing Cursiefen et al. 2004, Rodriguez-Manzaneque et al. 2001 V, skin fragility, increased vascularity and cortical Agah et al. 2002, Cursiefen et al. 2004, bone density, accelerated wound healing Hawighorst et al. 2001, Kyriakides et al. 1998 V, mild skeletal defects Hankenson et al. 2005 EL, heart segmentation defect Mjaatvedt et al. 1998 V, no obvious phenotype Zheng et al. 1995

Note. V, viable; EL, embryonic lethal; L, lethal; anaturally occuring mutations; bhypomorph mutations

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What Mouse Mutants Teach Us About Extracellular Matrix Function

What Mouse Mutants Teach Us About Extracellular Matrix Function

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