TGF BETA SIGNALING IN PALATAL GROWTH AND DIFFERENTIATION

描述(改编自研究人员摘要)：胚胎发育 哺乳动物的口面部依赖于复杂的组织相互作用， 形态发生运动、细胞分化增殖与细胞 分化，其中的许多方面受到转化的调节 生长因子β(TGF-Bs)。在转化生长因子-β的多效性作用中， 继发性腭裂发育对间充质细胞生长的抑制作用 和诱导内侧边缘上皮细胞分化，两者都是必要的 以保证正常的腭部发育。到目前为止，还没有研究涉及到 细胞质和核信号机制转导这一短期 旁分泌信号进入长期的表型改变，最终达到 在正常的味觉发育中。因此，目前的提案寻求 目的：阐明转化生长因子-B在腭部个体发育中作用的分子基础 确定介导转化生长因子-B作用的核信号通路 在这个胚胎组织中。对核监管机构进行的此类调查 基因表达对于理解正常上颌的生物学是必不可少的 发展并最终阐明各种不同的分子基础 腭部先天畸形。多个肿瘤抑制基因 产品，包括视网膜母细胞瘤蛋白Rb和Rb2/p130，已经被 被认为是生长和终末分化的调节者 胚胎发生。此外，视网膜母细胞瘤蛋白家族的成员有 已被发现介导生长抑制和终止 转化生长因子-B对几种成体细胞的诱导分化作用。 这些蛋白质是否参与形态发生和生长调节 转化生长因子-β在发育过程中的作用是一个耐人寻味但尚未回答的问题， 问题。因此，当前的应用程序建议调查 Rb和Rb2核蛋白在介导血管紧张素转换酶效应中的作用 转化生长因子-B对胚胎腭部组织生长分化的影响这个 描述了以下目标/假设以解决这种参与：1) 转化生长因子-B影响视网膜母细胞瘤(Rb和Rb2)基因的表达 胚胎腭部组织中的基因产物。2a)转化生长因子-B的作用 该组织是在Rb和Rb2蛋白磷酸化水平上被诱导的。 2b)转化生长因子-B诱导的Rb和Rb2蛋白磷酸化的改变是 通过一组离散的G1期细胞周期蛋白依赖的激酶、细胞周期蛋白 依赖的激酶抑制剂和/或丝氨酸-苏氨酸磷酸酶。3) Rb和Rb2在胚胎腭部组织中的下游作用是通过以下途径介导的 E2F转录因子家族。4)转化生长因子-β调控血管内皮生长因子的表达 视网膜母细胞瘤基因产物在小鼠胚胎味觉中的作用 间充质细胞生长和上皮分化。

DESCRIPTION (Adapted from the investigator's Abstract): 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.