TGF BETA SIGNALING IN PALATAL GROWTH AND DIFFERENTIATION

描述（改编自研究者摘要）： 哺乳动物口面区域依赖于复杂的组织相互作用， 形态发生运动、差异细胞增殖和细胞 分化，其中许多方面是由转化 生长因子β（TGF-β）。 在TGF-β的多效性作用中， 发育中的次生腭是间充质细胞生长的抑制 和诱导中缘上皮细胞分化，两者都是必要的 正常的腭发育 到目前为止，还没有研究涉及 细胞质和细胞核的信号机制， 旁分泌信号进入长期的表型改变， 在正常的腭发育中。 因此，目前的建议旨在 阐明TGF-β在腭发育过程中作用的分子基础， 定义介导TGF-β作用的核信号通路 在这个胚胎组织中。 对核监管机构的此类调查 基因表达对于理解正常腭的生物学是必不可少的 发展并最终阐明各种 先天性腭畸形。 一些抑癌基因 包括视网膜母细胞瘤蛋白Rb和Rb 2/p130在内的产品， 作为生长和终末分化的调节剂， 胚胎发生 此外，视网膜母细胞瘤蛋白家族的成员具有 被发现介导生长抑制和终端 TGF-β在几种成体细胞类型中的分化诱导作用。 这些蛋白质是否介导了形态发生和生长调节 TGF-β在发育过程中的作用是一个有趣的，但尚未回答， 问题 因此，本申请提出研究 Rb和Rb 2核蛋白在介导的作用， TGF-Bs对胚胎腭部组织生长和分化的影响 的 描述了以下目标/假设来解决这种参与：1） TGF-β影响视网膜母细胞瘤（Rb和Rb 2）基因的表达， 胚胎腭组织中的基因产物。 2a）TGF-B在小鼠中的作用 该组织在Rb和Rb 2蛋白磷酸化水平上被引发。 2b）TGF-B诱导的Rb和Rb 2蛋白磷酸化的改变， 通过一组离散的G1期细胞周期蛋白依赖性激酶，细胞周期蛋白 依赖性激酶抑制剂和/或丝氨酸-苏氨酸磷酸酶。 第三章 Rb和Rb 2在胚胎腭组织中的下游作用是由 转录因子E2 F家族。 4)TGF-B调节的 视网膜母细胞瘤基因产物在小鼠胚胎腭中的作用 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.