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Ellis-van Creveld (EvC) syndrome is a skeletal dysplasia, characterized by short limbs, postaxial polydactyly, and dental abnormalities. EvC syndrome is also categorized as a ciliopathy because of ciliary localization of proteins encoded by the two causative genes, EVC and EVC2 (aka LIMBIN). While recent studies demonstrated important roles for EVC/EVC2 in Hedgehog signaling, there is still little known about the pathophysiological mechanisms underlying the skeletal dysplasia features of EvC patients, and in particular why limb development is affected, but not other aspects of organogenesis that also require Hedgehog signaling. In this report, we comprehensively analyze limb skeletogenesis in Evc2 mutant mice and in cell and tissue cultures derived from these mice. Both in vivo and in vitro data demonstrate elevated Fibroblast Growth Factor (FGF) signaling in Evc2 mutant growth plates, in addition to compromised but not abrogated Hedgehog-PTHrP feedback loop. Elevation of FGF signaling, mainly due to increased Fgf18 expression upon inactivation of Evc2 in the perichondrium, critically contributes to the pathogenesis of limb dwarfism. The limb dwarfism phenotype is partially rescued by inactivation of one allele of Fgf18 in the Evc2 mutant mice. Taken together, our data uncover a novel pathogenic mechanism to understand limb dwarfism in patients with Ellis-van Creveld syndrome.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2007.04.048 Byline: Irene H. Hung, Kai Yu, Kory J. Lavine, David M. Ornitz Keywords: Fibroblast growth factor 9 (FGF9); Skeletal development; Growth plate; Chondrocyte; Osteoblast; Periosteum; Perichondrium; Vascular development Abstract: Gain-of-function mutations in fibroblast growth factor (FGF) receptors result in chondrodysplasia and craniosynostosis syndromes, highlighting the critical role for FGF signaling in skeletal development. Although the FGFRs involved in skeletal development have been well characterized, only a single FGF ligand, FGF18, has been identified that regulates skeletal development during embryogenesis. Here we identify Fgf9 as a second FGF ligand that is critical for skeletal development. We show that Fgf9 is expressed in the proximity of developing skeletal elements and that Fgf9-deficient mice exhibit rhizomelia (a disproportionate shortening of proximal skeletal elements), which is a prominent feature of patients with FGFR3-induced chondrodysplasia syndromes. Although Fgf9 is expressed in the apical ectodermal ridge in the limb bud, we demonstrate that the Fgf9.sup.-/- limb phenotype results from loss of FGF9 functions after formation of the mesenchymal condensation. In developing stylopod elements, FGF9 promotes chondrocyte hypertrophy at early stages and regulates vascularization of the growth plate and osteogenesis at later stages of skeletal development. Author Affiliation: Department of Molecular Biology and Pharmacology, Washington University School of Medicine, Campus Box 8103, 660 S. Euclid Avenue, St. Louis, MO 63110, USA Article History: Received 1 March 2007; Revised 5 April 2007; Accepted 30 April 2007

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2006.08.071 Byline: Zhonghao Liu, Kory J. Lavine, Irene H. Hung, David M. Ornitz Keywords: Fibroblast growth factor 18 (FGF18); Skeletal development; Growth plate; Chondrocyte; Osteoblast; Periosteum; Perichondrium; Vascular development Abstract: Fibroblast growth factor 18 (FGF18) has been shown to regulate chondrocyte proliferation and differentiation by signaling through FGF receptor 3 (FGFR3) and to regulate osteogenesis by signaling through other FGFRs. Fgf18.sup.-/- mice have an apparent delay in skeletal mineralization that is not seen in Fgfr3.sup.-/- mice. However, this delay in mineralization could not be simply explained by FGF18 signaling to osteoblasts. Here we show that delayed mineralization in Fgf18.sup.-/- mice was closely associated with delayed initiation of chondrocyte hypertrophy, decreased proliferation at early stages of chondrogenesis, delayed skeletal vascularization and delayed osteoclast and osteoblast recruitment to the growth plate. We further show that FGF18 is necessary for Vegf expression in hypertrophic chondrocytes and the perichondrium and is sufficient to induce Vegf expression in skeletal explants. These findings support a model in which FGF18 regulates skeletal vascularization and subsequent recruitment of osteoblasts/osteoclasts through regulation of early stages of chondrogenesis and VEGF expression. FGF18 thus coordinates neovascularization of the growth plate with chondrocyte and osteoblast growth and differentiation. Author Affiliation: Department of Molecular Biology and Pharmacology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA Article History: Received 9 June 2006; Revised 29 August 2006; Accepted 30 August 2006