FUNCTION OF PRB RELATED PROTEINS IN SKELETAL DEVELOPMENT

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DESCRIPTION (Adapted from the Applicant's Abstract): The control of chondrocyte differentiation and proliferation plays a central role in skeletogenesis. The retinoblastoma protein (pRB)-related p107 and p130 proteins are implicated in these processes, since mouse embryos that are deficient in p107 and p130 exhibited delayed chondrocyte differentiation and deregulated epiphyseal chondrocyte growth. The study is intended to establish the mechanisms through which p107 and p130 contribute to chondrocyte differentiation and proliferation control. The goals of this study are: (1) to identify the earliest features of embryonic chondrogenesis that require p107/p130 function, by identifying the first abnormalities in mesenchymal cell condensation morphology, proliferation control, and chondrogenesis-associated gene expression that occur in p107/p130-deficient embryos; (2) to identify genes related to the control of chondrogenesis whose normal regulation depends upon p107/p130 function, by identifying genes that are differentially expressed in wild-type and 107/p130-deficient embryos; (3) to establish whether the induction of chondrogenesis by TGF-beta-like proteins requires p107/p130 function, by determining whether such induction is impaired, in vitro, in p107/p130-deficient mesenchymal cells; (4) to determine how p107/p130 function is engaged in early chondrogenesis, and in epiphyseal chondrocyte cell cycle withdrawal, by establishing the normal expression patterns of p107, p130 and putative regulators of p107 and p130; and (5) to determine how p107 and p130 impose control on epiphyseal chondrocyte proliferation, by identifying genes that are deregulated in epiphyseal chondrocytes of p107/p130-deficient embryos. These studies are intended to improve our understanding of cell growth and differentiation control processes that are of wide-ranging importance in endochondral bone development.