TGFbeta/Bmp Signaling during Mammalian Lens Development

产品说明：透镜的发育过程为研究细胞增殖、分化、迁移和程序性细胞死亡的分子机制提供了一个很好的模型系统，这些是器官发生过程中的基本过程。在脊椎动物中，透镜的诱导和分化涉及由几个进化保守的蛋白质家族所扮演的高度协调的角色，其中许多涉及人类和动物模型中的各种先天性缺陷。该提案的目标是确定哺乳动物透镜发育过程中由分泌信号分子的转化生长因子（TGF）超家族启动的信号通路的作用。最近的遗传和发育研究已经清楚地证明了TGF β超家族途径在透镜发育中的整体功能贡献。然而，由于组织相互作用过程对眼睛发育的复杂调节以及一些相关信号传导组分之间的潜在混杂性和冗余性，这些信号传导途径在体内调节的精确靶组织和下游遗传程序仍然不清楚。为了解决这个问题，我们提出进行一系列实验，以1）测试Alk 2受体是否在透镜发育期间起积极作用，2）确定在透镜诱导期间需要Alk 3介导的信号传导的主要靶组织类型，和3）测试Smad 4在透镜发育期间起多种作用的假设。我们将采用遗传学方法，使用小鼠作为模型系统，以更精确地绘制这些TGF β信号通路组分在描述透镜发育的遗传调控网络的现有模型上的功能坐标。这些研究将在透镜发育过程中以空间和时间特定方式从遗传学上定义TGF β信号通路的关键单个组分的功能。因此，这些研究的结果将有助于我们更好地了解控制正常透镜发育的分子机制和人类各种眼睛缺陷的原因。

DESCRIPTION: The process of lens development has provided an excellent model system to study the molecular mechanisms of cellular proliferation, differentiation, migration, and programmed cell death, which are fundamental processes during organogenesis. In vertebrates, induction and differentiation of the lens involve highly orchestrated roles played by several evolutionary conserved families of proteins, many of which are implicated in various congenital defects both in humans and animal models. The goal of this proposal is to define the role of signaling pathways initiated by the transforming growth factor ¿ (TGF¿) superfamily of secreted signaling molecules during mammalian lens development. Recent genetic and developmental studies have clearly demonstrated overall functional contribution of the TGF¿ superfamily pathways in lens development. However, due to complex regulation of eye development by tissue interaction processes and potential promiscuity and redundancy among some of the related signaling components, precise target tissues and downstream genetic programs that these signaling pathways regulate in vivo are still poorly defined. To approach this question, we propose to carry out a series of experiments, in order to 1) test whether Alk2 receptor plays an active role during lens development, 2) to define the primary target tissue type that requires Alk3-mediated signaling during lens induction, and 3) to test the hypothesis that Smad4 plays multiple roles during lens development. We will take genetic approaches using the mouse as a model system, to map more precisely the functional coordinates of these TGF¿ signaling pathway components on the present models describing the genetic regulatory network of lens development. These studies will genetically define the function of key individual components of the TGF¿ signaling pathways in spatially and temporally specified manners during lens development. The outcome from these studies will, thus, contribute to our better understanding of the molecular mechanisms controlling normal lens development and causes of various eye defects in humans.