Role of the Foxn4 Gene during Retinogenesis

描述（由申请人提供）：本提案的长期目标是了解在哺乳动物视网膜发生过程中导致不同细胞类型的命运承诺和分化的分子事件。无突细胞和水平细胞是视网膜回路中调节和整合视觉信号的两类重要的中间神经元。然而，尽管它们具有生理意义，但目前对其发育的分子基础仍知之甚少。在这个应用中，实验将集中在Foxn4上，Foxn4是一种叉头/翼螺旋转录因子，在分裂视网膜祖细胞的一个子集中表达，该子集的命运偏向于无毛细胞和水平细胞。根据我们的初步研究，我们推测Fonx4可能在这两种细胞类型的能力获得和命运承诺中发挥关键作用。

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to understand the molecular events that lead to fate commitment and differentiation of different cell types during mammalian retinogenesis. The amacrine and horizontal cells are two classes of important interneurons that modulate and integrate visual signals in the retinal circuitry. Despite their physiological significance, however, the molecular bases underlying their development remain poorly understood at present. In this application, experiments are proposed that will focus on Foxn4, a forkhead/winged helix transcription factor that is expressed in a subset of dividing retinal progenitor cells characteristic of the subset with a fate biased toward amacrine and horizontal cells. Based on our preliminary studies it has been speculated that Fonx4 may play a key role in competence acquisition and fate commitment of these two cell types. The studies outlined in this proposal are designed to provide an integrated approach toward a comprehensive understanding of the biological function of Foxn4 during retinogenesis. Four specific aims will be pursued: i) to investigate the role of Foxn4 during retinal development by overexpression in progenitor cells. These studies aim to explore the function of Foxn4 during mammalian retinogenesis using a gain-of-function approach involving retrovirus-mediated overexpression of Foxn4 in the mouse retina; ii) to study the biological function of Foxn4 during retinal development by targeted gene disruption. The proposed experiments aim to uncover the role of Foxn4 during retinogenesis using a loss-of-function approach involving the production and characterization of Foxn4 knockout mice; iii) to analyze the relationship between Foxn4 and other retinogenic factors mediating amacrine and horizontal cell development. These studies aim to test the hypothesis that Foxn4 alone or in combination with a redundant factor, may control the genesis of amacrine and horizontal cells by activating the expression of retinogenic factors involved in the specification of these two cell types; and iv) to map the fate of Foxn4-expressing retinal progenitors. The goal is to use the Cre-loxP fate-mapping strategy to test the hypothesis that the subset of Foxn4-expressing retinal progenitors may represent those with a fate biased toward amacrine and horizontal cells. Taken together, these proposed studies are expected to provide important novel insights into the genetic regulatory networks that govern the development of different retinal cell types and may provide the foundation for better understanding and treatment of neuroretinal diseases.