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Perlecan is essential for cartilage and cephalic development

Nature Genetics volume 23, pages 354–358 (1999)Cite this article

Abstract

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 signalling1,2,3,4,5. Perlecan is present in a variety of basement membranes and in other extracellular matrix structures5,6. 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 mice10,11. Our findings suggest that these molecules affect similar signalling pathways.

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Figure 1: Targeted disruption of Hspg2 and generation of chimaeras.
Figure 2: Gross appearance of wild-type (a,c,e) and Hspg2–/– mice (b,d,f, g).
Figure 3: Skeletal preparations of wild-type (a,c,e, g,i,k) and Hspg2–/– ( b,d,f,h,j,l) newborn mice stained with Alcian blue and Alizarin red.
Figure 4: Abnormal chondrocyte proliferation and differentiation in Hspg2–/– mice.
Figure 5: Abnormal cartilage matrix formation of Hspg2–/– mice.
Figure 6: Expressions of perlecan, Fgfr3 and Fgf1.

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Acknowledgements

We thank G. Longenecker for blastocyst injection; W. Swaim, N. Marinos, V. Morgan, L. Bowers and R. Yaskovich for histology and electron microscopy; M. Mankani for Faxitron radiographs; J. Sasse for Fgf1 antibody; C. Deng for Fgfr3 cDNA; A. McMahon for Ihh cDNA; G. Lunstrum and N. Morris for collagen X antibody; A. Kulkarni, S. Kimura, T. Oshima, M. Hirasawa and K. Kimata for technical comments; and H. Kleinman for critically reading the manuscript. Some of this work was supported by a grant from Seikagaku Corporation.

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Authors and Affiliations

  1. Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA

    Eri Arikawa-Hirasawa, Hideto Watanabe, Hiroya Takami & Yoshihiko Yamada

  2. Shriners Hospital for Children, Tampa, Florida, USA

    John R. Hassell

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Correspondence to Yoshihiko Yamada.

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Arikawa-Hirasawa, E., Watanabe, H., Takami, H. et al. Perlecan is essential for cartilage and cephalic development. Nat Genet 23, 354–358 (1999). https://doi.org/10.1038/15537

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