MEDIATORS OF TGF BETA SIGNALING IN PALATE DEVELOPMENT

目的：阐明转化生长因子β在腭部发育过程中对细胞增殖和分化的影响及其信号传导途径。口腔面部的胚胎发育需要精确的增殖和分化模式。这些过程的中心是细胞周期，它的功能是整合大量传入的信息，并协调导致分裂或分化的复杂的细胞质和核过程。细胞周期的关键调节因子之一是E2F转录因子家族，它的功能是控制那些通过限制点所必需的基因的表达，以及随后在S阶段遗传物质的复制。E2F的活性受多种因素控制，包括与视网膜母细胞瘤基因家族(pRb，p107，p130)的产物形成复合体。虽然E2F和PRB在生长和分化障碍(如恶性肿瘤)中的作用已知很多，但它们在腭部发育中的作用以及各种生长因子对其功能的影响尚不清楚。对发育中的腭部有深远影响的生长因子之一是转化生长因子β，它抑制细胞增殖，刺激腭间充质细胞合成细胞外基质，同时也诱导内侧缘上皮的分化。由于已知在其他组织和细胞类型中，TGFβ影响细胞周期的多个组成部分(包括PRBS和E2F)，我们的假设是，TGFβ通过阻止细胞周期而影响颅面部发育，这是由E2F转录因子家族的表达和活性以及E2F和RB磷蛋白家族之间相互作用的改变所介导的。

To elucidate the signal transduction pathway (molecular and nuclear mechanisms of gene regulation) responsible for the effects of TGFbeta on proliferation and differentiation during palatal development. The embryonic development of the orofacial area requires precise patterns of proliferation and differentiation. Central to these processes is the cell cycle which functions to integrate the vast array of incoming information and to coordinate the complex cytoplasmic and nuclear processes leading to either division or differentiation. One of the pivotal regulators of the cell cycle is the E2F family of transcription factors which functions to control the expression of those genes necessary for passage through the restriction point and the subsequent replication of genetic material during the S phase. The activity of E2F is controlled by a number of factors including formation of complexes with the products of the Retinoblastoma gene family (pRb, p107, p130). Although much is known concerning the role of E2Fs and pRbs in disturbances of growth and differentiation such as malignancy, their role in palatal development and the effects of various growth factors on their function has yet to be delineated. One growth factor having profound effects on the developing palate is TGFbeta which inhibits cellular proliferation and stimulates synthesis of extracellular matrix in palatal mesenchymal cells while also inducing differentiation of the medial edge epithelium. Since TGFbeta is known to affect multiple components of the cell cycle (including the pRbs and E2Fs) in other tissues and cell types, our hypothesis is that TGFbeta influences craniofacial development via an arrest of the cell cycle which is mediated by changes in the expression and the activity of the E2F family of transcription factors and by alterations in the interactions between the E2Fs and the Rb family of phosphoproteins.