Transcriptional regulation of retinal cell differentiation and function

描述（由申请人提供）：脊椎动物视网膜是一个强大的模型系统，用于解决在发育过程中如何指定单个细胞亚型的机制问题。我们发现同源结构域转录因子Lhx2调控着视网膜Muller胶质细胞的发育和功能。Lhx2的功能丧失会导致Muller胶质发育的严重缺陷。此外，成熟Muller胶质细胞中Lhx2的选择性缺失导致许多已知在Muller胶质细胞中表达的基因表达改变。此外，这些细胞在失去Lhx2后变得构成性反应，模仿损伤的效果。我们建议在成熟的Muller胶质细胞中鉴定由Lhx2直接调控的基因，并研究这种构成性反应在未损伤和损伤视网膜中的后果。我们将确定在成熟Muller胶质细胞中选择性缺乏Lhx2表达的小鼠是否表现出完全具有反应状态特征的基因表达谱，并确定Lhx2是否直接抑制激活胶质细胞中表达的基因表达。由于神经胶质反应性已被提出调节光感受器的活力，我们将对成熟Muller神经胶质中Lhx2缺失后突变动物整个生命周期中发生的细胞变化进行详细检查。此外，我们将确定成熟胶质细胞特异性缺失Lhx2在光感受器损伤模型中的作用。最后，我们将描述从lhx2缺陷胶质细胞释放的调节光感受器存活的分子信号。

DESCRIPTION (provided by applicant): The vertebrate retina is a powerful model system for addressing mechanistic questions of how individual cell subtypes are specified during development. We have found that the homeodomain transcription factor Lhx2 regulates the development and function of retinal Muller glia. Loss of function of Lhx2 results in dramatic defects in Muller glial development. Furthermore, selective deletion of Lhx2 in mature Muller glia leads to altered expression of many genes known to be expressed in Muller glia. Furthermore, these cells becoming constitutively reactive following loss of Lhx2, mimicking the effect of injury. We propose to both identify the genes which are directly regulated by Lhx2 in mature Muller glia, and to examine the consequences of this constitutive reactivity in both uninjured and injured retina. We will determine whether mice that selectively lack Lhx2 expression in mature Muller glia demonstrate a gene expression profile that is fully characteristic of a reactive state, and determine whether Lhx2 directly represses expression of genes expressed in activated glia. Since glial reactivity has been proposed to regulate photoreceptor viability, we will conduct a detailed examination of cellular changes that occur throughout the lifespan of mutant animals following deletion of Lhx2 in mature Muller glia. Furthermore, we will determine the effects of mature glia- specific deletion of Lhx2 in models of photoreceptor injury. Finally, we will characterize any molecular signals released from Lhx2-deficient glia that regulate photoreceptor survival. PUBLIC HEALTH RELEVANCE: The vertebrate retina is a powerful model system for addressing mechanistic questions of how individual cell subtypes are specified during development. We have found that the homeodomain transcription factor Lhx2 regulates the expression of genes in retinal Muller glia, which provide support and sustenance to neurons of the retina. Furthermore, selective deletion of Lhx2 in mature Muller glia leads to these cells becoming constitutively reactive, mimicking the effect of injury. We propose to identify the molecular targets of Lhx2 in Muller glia. We will also investigate the functional consequences of Lhx2 deletion in mature Muller glia, and determine whether constitutive glial reactivity regulates photoreceptor survival following retinal injury.