Transcriptional regulation of retinal cell differentiation and function

描述(申请人提供)：视网膜Muller神经胶质细胞在调节视网膜神经元损伤后的存活中发挥关键作用，并可能成为视网膜营养不良的基于细胞的再生治疗的有用来源。在过去的几年里，我们已经建立了前体和神经胶质表达的同源结构域转录因子LHX2，作为Muller神经胶质发育和功能的多个不同方面的重要调节因子。在新生视网膜祖细胞中，LHX2以牺牲神经发生为代价促进神经发生，但当LHX2在有丝分裂后神经前体细胞中表达时，对神经胶质分化是必不可少的。LHX2还在终末分化的Muller胶质细胞中发挥作用，既抑制肥厚性胶质增生症诱导的基因表达，又促进损伤后胶质源性神经保护因子的表达。我们的目标是研究允许LHX2执行这一不同范围的调节功能的分子机制。我们的目标是全面分析视网膜前体细胞、神经胶质前体细胞以及成熟的静息和反应性Muller胶质细胞中的LHX2 DNA结合模式。我们将使用这些数据 结合这些细胞类型的mRNA表达数据，确定选择性和差异性调节LHX2功能的候选辅助因子，并使用体内电穿孔和靶向遗传方法证实这一点。我们最终打算利用这些发现来确定是否可以通过操纵LHX2活性来诱导胶质细胞去分化，或者增强视网膜玻璃的神经保护功能。

DESCRIPTION (provided by applicant): Retinal Muller glia play a critical role in regulating the survival of retinal neurons following damage, and may be a useful source for cell-based regenerative therapies for retinal dystrophies. Over the past few years, we have established the progenitor and glial-expressed homeodomain transcription factor Lhx2 as an essential regulator of multiple different aspects of Muller glial development and function. In neonatal retinal progenitors, Lhx2 promotes neurogenesis at the expense of gliogenesis, but Lhx2 is essential for glial differentiation when expressed in postmitotic glial precursors. Lhx2 also functions in terminally differentiated Muller glia to both repress expression of genes induced in hypertrophic gliosis and promote expression of glial-derived neuroprotective factors following injury. We aim to investigate the molecular mechanisms that allow Lhx2 to perform this diverse range of regulatory functions. We aim to comprehensively profile Lhx2 DNA binding patterns in retinal progenitors, glial precursors and in mature resting and reactive Muller glia. We will use this data together with mRNA expression data from these cell types to identify candidate cofactors that selectively and differentially regulate Lhx2 function, and confirm this using both in vivo electroporation and targeted genetic approaches. We ultimately intend to use these findings to determine if glial dedifferentiation can be induced, or the neuroprotective functions of retinal gla enhanced, by manipulating Lhx2 activity.