Perlecan is essential for cartilage and cephalic development.
Perlecan, a large, multi-domain, heparan sulfate proteoglycan originally identified in basement membrane, interacts with extracellular matrix proteins, growth factors and receptors, and influences cellular signalling. Perlecan is present in a variety of basement membranes and in other extracellular matrix structures. We have disrupted the gene encoding perlecan (Hspg2) in mice. Approximately 40% of Hspg2-/- mice died at embryonic day (E) 10.5 with defective cephalic development. The remaining Hspg2-/- mice died just after birth with skeletal dysplasia characterized by micromelia with broad and bowed long bones, narrow thorax and craniofacial abnormalities. Only 6% of Hspg2-/- mice developed both exencephaly and chondrodysplasia. Hspg2-/- cartilage showed severe disorganization of the columnar structures of chondrocytes and defective endochondral ossification. Hspg2-/- cartilage matrix contained reduced and disorganized collagen fibrils and glycosaminoglycans, suggesting that perlecan has an important role in matrix structure. In Hspg2-/- cartilage, proliferation of chondrocytes was reduced and the prehypertrophic zone was diminished. The abnormal phenotypes of the Hspg2-/- skeleton are similar to those of thanatophoric dysplasia (TD) type I, which is caused by activating mutations in FGFR3 (refs 7, 8, 9), and to those of Fgfr3 gain-of-function mice. Our findings suggest that these molecules affect similar signalling pathways.
Arikawa-Hirasawa
E
E
Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
Watanabe
H
H
Takami
H
H
Hassell
J R
JR
Yamada
Y
Y
D000015:Abnormalities, Multiple / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002356:Cartilage / Q000002:abnormalities / Q000196:embryology / Q000254:growth & development* / Q000378:metabolism; D064236:Cartilage Oligomeric Matrix Protein; D002454:Cell Differentiation; D002455:Cell Division; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000032:analysis; D017353:Gene Deletion; D015870:Gene Expression; D006023:Glycoproteins / Q000032:analysis; D006132:Growth Plate / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D006257:Head / Q000002:abnormalities / Q000196:embryology / Q000254:growth & development*; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D064235:Matrilin Proteins; D051379:Mice; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional; D011505:Protein-Tyrosine Kinases; D011509:Proteoglycans / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D013796:Thanatophoric Dysplasia / Q000235:genetics
D064236:Cartilage Oligomeric Matrix Protein; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D064235:Matrilin Proteins; D011505:Protein-Tyrosine Kinases; D011509:Proteoglycans; D012333:RNA, Messenger; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor; C577540:Matn1 protein, mouse; C577553:TSP5 protein, human; C071927:perlecan; C496365:FGFR3 protein, human; C496366:Fgfr3 protein, mouse