Integrative Analysis of Vertebrate Retinal Lamination

描述（由申请人提供）：在视网膜发育期间，神经上皮祖细胞从对称增殖模式（其中两个子细胞均保持在有丝分裂周期中）转变为神经发生模式（其中至少一个子细胞退出细胞周期并分化为神经元（或后来分化为神经胶质细胞））。在脊椎动物神经系统中促进神经原性分裂的细胞机制仍然未知。最近的一些观察表明，在调节视网膜内的神经发生的运动间核迁移（IKNM）和极化信号的基本作用。IKNM是其中神经上皮细胞核与有丝分裂周期同相地从顶面到基底面振荡的过程。我们将研究细胞周期的特定阶段和祖细胞中细胞核的顶基位置如何影响神经源性细胞分裂的选择，并最终促进正常的视网膜分层。在我们的研究中，我们也将探讨极化信号在视网膜发生过程中的影响。这项研究将为视网膜祖细胞的信号整合和细胞命运承诺提供基本的见解。由于这项研究的基本性质，我们的结果与视网膜干细胞操作和疾病过程都相关。公共卫生相关性：该提案概述了旨在了解祖细胞如何被选择以产生神经元的机制的实验。这一过程的基础知识对于指导干细胞生物学、再生医学和视网膜疾病的进一步研究非常重要。

DESCRIPTION (provided by applicant): During retinal development, neuroepithelial progenitor cells switch from a symmetric proliferative mode, where both daughter cells remain in the mitotic cycle, to a neurogenic mode, where at least one of the daughter cells exits the cell cycle and differentiates as a neuron (or later as a glial cell). The cellular mechanisms that promote neurogenic divisions in the vertebrate nervous system remain unknown. Several recent observations demonstrate a fundamental role for interkinetic nuclear migration (IKNM) and polarized signals in regulating neurogenesis within the retina. IKNM is the process in which neuroepithelial nuclei oscillate from the apical to basal surface in phase with the mitotic cycle. We will investigate how specific phases of the cell cycle and the apical-basal position of the nucleus in progenitor cells impact the selection of neurogenic cell divisions and ultimately facilitate normal retinal lamination. In our studies, we will also investigate the influence of polarized signals during retinogenesis. This research will provide fundamental insights into signal integration and cell-fate commitment of retinal progenitor cells. Because of the fundamental nature of this research, our results have relevance to both retinal stem cell manipulation and disease processes. PUBLIC HEALTH RELEVANCE: This proposal outlines experiments to understand the mechanisms for how progenitor cells are selected to generate neurons. Fundamental knowledge of this process is important for guiding further research on stem cell biology, regenerative medicine, and retinal disease.