TGFbeta/Bmp Signaling during Mammalian Lens Development

描述：晶状体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，这些都是器官发生中的基本过程。在脊椎动物中，晶状体的诱导和分化涉及几个进化保守的蛋白质家族所扮演的高度协调的角色，其中许多蛋白质与人类和动物模型中的各种先天性缺陷有关。这项研究的目的是确定由转化生长因子(TGF)超家族分泌的信号分子启动的信号通路在哺乳动物晶状体发育中的作用。最近的遗传和发育研究清楚地证明了转化生长因子超家族通路在晶状体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控，以及一些相关信号成分之间潜在的混杂和冗余，这些信号通路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，我们计划进行一系列实验，以测试Alk2受体是否在晶状体发育过程中发挥积极作用，2)确定在晶状体诱导过程中需要Alk3介导的信号转导的主要靶组织类型，以及3)验证Smad4在晶状体发育过程中发挥多重作用的假设。我们将采用遗传学方法，以小鼠为模型系统，在目前描述晶状体发育遗传调控网络的模型上，更准确地映射这些转化生长因子信号通路组件的功能坐标。这些研究将以空间和时间指定的方式从基因上定义晶状体发育过程中转化生长因子信号通路的关键个体成分的功能。因此，这些研究的结果将有助于我们更好地理解控制人类正常晶状体发育的分子机制和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.