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.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
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Oral Biology and Medicine Subcommittee 1 (OBM)
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Thomas Jefferson University
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Warner, Dennis R; Smith, Henry S; Webb, Cynthia L et al. (2009) Expression of Wnts in the developing murine secondary palate. Int J Dev Biol 53:1105-12
Warner, Dennis R; Horn, Kristin H; Mudd, Lisa et al. (2007) PRDM16/MEL1: a novel Smad binding protein expressed in murine embryonic orofacial tissue. Biochim Biophys Acta 1773:814-20
Warner, D R; Pisano, M M; Greene, R M (2006) Functional analysis of CBP/p300 in embryonic orofacial mesenchymal cells. J Cell Biochem 99:1374-9
Warner, D R; Greene, R M; Pisano, M M (2005) Interaction between Smad 3 and Dishevelled in murine embryonic craniofacial mesenchymal cells. Orthod Craniofac Res 8:123-30
Warner, Dennis R; Greene, Robert M; Pisano, M Michele (2005) Cross-talk between the TGFbeta and Wnt signaling pathways in murine embryonic maxillary mesenchymal cells. FEBS Lett 579:3539-46
Greene, Robert M; Pisano, M Michele (2005) Recent advances in understanding transforming growth factor beta regulation of orofacial development. Hum Exp Toxicol 24:1-12
Greene, Robert M; Pisano, M Michele (2004) Perspectives on growth factors and orofacial development. Curr Pharm Des 10:2701-17
Warner, Dennis R; Bhattacherjee, Vasker; Yin, Xiaolong et al. (2004) Functional interaction between Smad, CREB binding protein, and p68 RNA helicase. Biochem Biophys Res Commun 324:70-6
Bhattacherjee, Vasker; Greene, Robert M; Michele Pisano, M (2003) Divergence of epidermal growth factor - transforming growth factor beta signaling in embryonic orofacial tissue. In Vitro Cell Dev Biol Anim 39:257-61
Warner, Dennis R; Roberts, Emily A; Greene, Robert M et al. (2003) Identification of novel Smad binding proteins. Biochem Biophys Res Commun 312:1185-90

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