Transcription Factor Control of Neuronal Diversity

摘要 抑制性神经元和兴奋性神经元之间的平衡是在发育早期建立的 转录激活因子PTF1a和转录激活因子PTF1a之间的相互作用主导的过程 抑制物PRDM13存在于神经系统的多个区域。最初的细胞命运决定 最终引起背侧脊髓、小脑和视网膜的抑制性神经元依赖 这些决定命运的转录因子(TF)的早期活性。PTF1a，就像其他早期的- 作用基本螺旋-环-螺旋(BHLH)因子，通过触发 下游的基因级联。这样的TF通过限制祖先产生了深远的影响 在成熟神经元出现之前很久就有发育潜力。在没有的情况下 PTF1A，神经前体细胞不能产生抑制性神经元，并异常地假设 兴奋性神经元的命运。因此，PTF1A表达的空间和时间控制控制着 多个神经元回路中抑制/兴奋平衡的形成。在目标1中，我们将 检查Ptf1a的背神经管特异性增强子的体内需求 分子、细胞和行为水平。PRDM13，转录抑制因子和直接抑制因子 PTF1a的靶标，通过以下方式确保脊髓背侧抑制神经元的正确规格 抑制对指定替代兴奋性神经元命运至关重要的基因。因为 PRDM因子可以具有甲基转移酶活性和/或可以招募其他染色质修饰 酶，而PRDM13可能与bHLHTF结合，PRDM13可能在 这些因素和伴随的表观遗传格局的变化在神经元亚型- 规格。事实上，PRDM13与PTF1a和另一个bHLH结合了许多相似的基因组位点 因数ASCL1。在目标2和目标3中，我们将探讨PRDM13在神经发育中的作用 系统，并测试PRDM13被招募到bHLH结合位点的假设，以促进 抑制染色质的修饰，通过这些位点抑制转录。

Summary The balance between inhibitory and excitatory neurons is established early in development in a process dominated by the interplay between the transcriptional activator PTF1A and the repressor PRDM13 in multiple regions of the nervous system. Initial cell fate decisions that ultimately give rise to inhibitory neurons in the dorsal spinal cord, cerebellum, and retina depend on the early activity of these fate-specifying transcription factors (TFs). PTF1A, like other early- acting basic helix-loop-helix (bHLH) factors, acts as a `master regulator' by triggering downstream genetic cascades. Such TFs have profound effects by restricting progenitor developmental potential long before the appearance of mature neurons. In the absence of PTF1A, neural progenitors fail to generate inhibitory neurons and aberrantly assume an excitatory neuronal fate. Thus, the spatial and temporal control of PTF1A expression controls the formation of the inhibitory/excitatory balance in multiple neuronal circuits. In Aim 1 we will examine the in vivo requirement for a dorsal neural tube specific enhancer for Ptf1a at the molecular, cellular, and behavioral levels. PRDM13, a transcriptional repressor and a direct target of PTF1A, ensures correct specification of dorsal spinal cord inhibitory neurons by repressing genes essential for specifying the alternative excitatory neuronal fates. Because PRDM factors can have methyltransferase activity and/or can recruit other chromatin modifying enzymes, and PRDM13 may bind to bHLH TFs, PRDM13 may provide a molecular link between these factors and accompanying changes in the epigenetic landscape during neuronal subtype- specification. Indeed, PRDM13 binds many similar genomic sites as PTF1A and another bHLH factor ASCL1. In Aims 2 and 3, we will probe PRDM13 functions in the developing nervous system, and test the hypothesis that PRDM13 is recruited to bHLH bound sites to facilitate repressive chromatin modifications to repress transcription through these sites.