Transcriptional regulation of retinal cell differentiation and function

描述（由申请人提供）：视网膜Muller神经胶质在调节视网膜神经元损伤后的存活中起关键作用，可能是视网膜营养不良的细胞再生治疗的有用来源。在过去的几年里，我们已经确定了祖细胞和胶质表达的同源结构域转录因子Lhx2是Muller胶质发育和功能多个不同方面的重要调节因子。在新生儿视网膜祖细胞中，Lhx2促进神经发生，但Lhx2在有丝分裂后胶质前体中表达时对胶质分化至关重要。Lhx2在终末分化的Muller胶质细胞中也有抑制肥厚性胶质细胞增生诱导基因的表达和促进损伤后胶质源性神经保护因子的表达的功能。我们的目标是研究允许Lhx2执行这种不同范围的调节功能的分子机制。我们的目标是全面分析Lhx2 DNA结合模式在视网膜祖细胞，胶质前体细胞和成熟的休息和反应Muller胶质细胞。我们将使用这些数据

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.