Embryogenesis of the mammalian orofacial region is dependent on complex tissue interactions, morphogenetic movements, differential cell proliferation and cellular differentiation, many facets of which are regulated by the transforming growth factors beta (TGF-Bs). Among TGF-B's pleiotropic effects in the developing secondary palate are the inhibition of mesenchymal cell growth and induction of medial edge epithelial cell differentiation, both necessary for normal palatogenesis. No studies, to date, have addressed the cytoplasmic and nuclear signaling mechanisms which transduce this short-term paracrine signal into the long term phenotypic alterations which culminate in normal palate development. As such, the current proposal seeks to elucidate the molecular basis of TGF-Bs action during palatal ontogenesis by defining the nuclear signaling pathways mediating the effects of the TGF-Bs in this embryonic tissue. Such investigations into nuclear regulators of gene expression are essential for understanding the biology of normal palate development and ultimately elucidating the molecular basis of various congenital abnormalities of the palate. A number of tumor suppressor gene products, including the retinoblastoma proteins Rb and Rb2/p130, have been implicated as regulators of growth and terminal differentiation during embryogenesis. Moreover, members of the retinoblastoma protein family have been found to mediate the growth inhibitory and terminal differentiation-inducing effects of the TGF-Bs in several adult cell types. Whether these proteins mediate the morphogenetic and growth regulatory effects of TGF-B during development is an intriguing, yet unanswered, question. The current application, therefore, proposes to investigate the role of the Rb and Rb2 nuclear proteins in mediating the effects of the TGF-Bs on growth and differentiation of embryonic palatal tissue. The following aims/hypotheses are delineated to address this involvement: 1) TGF-Bs affect the expression of the retinoblastoma (Rb and Rb2) genes and gene products in embryonic palatal tissues. 2a) Effects of the TGF-Bs in this tissue are elicited at the level of Rb and Rb2 protein phosphorylation. 2b) TGF-B induced alterations in Rb and Rb2 protein phosphorylation are executed via a discrete set of G1-phase cyclin dependent kinases, cyclin dependent kinase inhibitors, and/or serine-threonine phosphatases. 3) Downstream effects of Rb and Rb2 in embryonic palatal tissue are mediated by the E2F family of transcription factors. 4) TGF-B regulated expression of the retinoblastoma gene products plays a role in murine embryonic palate mesenchymal cell growth and epithelial differentiation.
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