Molecular Control of Cortical Projection Neuron Identity and Connectivity

描述(申请人提供)：完成和发展复杂的认知和运动任务的能力取决于大脑皮层内以及皮质和大脑其他区域之间突触连接的准确性和复杂性。兴奋性投射(锥体)神经元的轴突投射构成整个大脑皮层的运动输出，并直接影响行为。调节不同皮质投射神经元的分子同一性和连接性的分子机制正在被解开。我们的目标是确定对锥体神经元的迁移、分子识别和连接至关重要的机制，并利用各种分子和遗传学方法研究它们的功能作用。在过去的四年里，我们在这笔赠款的支持下发表的初步研究已经从功能上表征了几个编码转录因子和轴突导向的基因，这些基因控制着皮质投射神经元发育的不同方面，如它们的分子识别、板层位置、树突树枝形成和轴突投射。在这项应用中，我们打算进一步描述其中一些基因发挥作用的细胞和分子机制。具体地说，拟议的实验旨在确定Sox5如何控制早期出生的皮质下投射神经元迁移到适当的板层位置并延长轴突投射(Aim1)；Fezf2的层特异性表达以及随后的投射神经元的分子鉴定如何受到上游转录调控因子(AIM2)的内在调控；以及在胚胎发育后期，与皮质下靶点(如丘脑)形成的轴突连接如何控制细胞外基因的表达(Aim3)。

DESCRIPTION (provided by applicant): The ability to accomplish and develop complex cognitive and motor tasks depends on the accuracy and intricacy of synaptic connections both within the cerebral cortex and between the cortex and other regions of the brain. Axonal projections of excitatory projection (pyramidal) neurons constitute the motor output of the entire cortex and directly influence behavior. Molecular mechanisms regulating the molecular identity and connectivity of distinct cortical projection neurons are being unraveled. Our goal is to identify mechanisms that are important for the migration, molecular identity and connectivity of pyramidal neurons, and to investigate their functional roles using a variety of molecular and genetic approaches. Our published and preliminary studies, supported by this grant in the last four years, have functionally characterized several genes encoding transcription factors and axon guidance that control different aspect of cortical projection neuron development, such as their molecular identity, laminar position, dendritic arborization, and axonal projections. In this application we intend to further characterize the cellular and molecular mechanisms by which some of these genes function. Specifically, the proposed experiments are designed to determine how Sox5 controls early-born subcortical projection neurons migration to their proper laminar positions and extend axonal projections (Aim1); how layer-specific expression of Fezf2 and subsequently the molecular identity of projection neurons are controlled cell-intrinsically by upstream transcriptional regulators (Aim2); and how formation of axonal connections with subcortical targets, such as the thalamus, controls gene expression cell-extrinsically in cortical projection neurons during late embryogenesis (Aim3).