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. ? ? ? ? ?
