Ctip2 Function in Corticospinal Motor Neuron Development

描述（由申请人提供）：拟议实验的长期目标是阐明新皮层投射神经元回路的神经元亚型特异性发育和修复病变的新皮层投射神经元。在哺乳动物端脑发育过程中，空间和时间异质性的祖细胞产生丰富多样的投射神经元亚型。尽管对祖细胞区域的关键分子控制已被广泛表征，但对有丝分裂后神经元中调节投射神经元亚型身份获得的基因的研究只是相对最近才开始。最近在Macklis实验室的工作（Arietta et al., Neuron '05; Molyneaux et al., Neuron '05; Ozdinler and Macklis, Nature Neurosci）。06年;Molyneaux等人。自然，神经科学。07年;Arietta et al.， J.神经科学。, 08年;赖等人……神经元的08年;Joshi et al., Neuron '08；Azim等人，2009年，Srubeck Tomassy等人，2009年)，通过其他研究人员的工作补充和扩展，已经确定了转录因子控制的组合程序，控制皮层投射神经元从祖细胞的分化和分化。其中一个这样的转录因子，COUP-TF相互作用蛋白2 （Ctip2）已经被我们的实验室证明对新皮层的皮质脊髓运动神经元（CSMN）（以及相关的脑下投射神经元）和纹状体的中等棘神经元（MSN）的分化至关重要；然而，Ctip2在这些重要的神经元类型中执行的特定分子分化程序是未知的。在本提案中，我概述了一个研究计划，旨在研究Ctip2在CSMN开发中的功能。我建议：1)确定Ctip2在CSMN轴突延伸和束状化中的具体作用；2)描述Ctip2在CSMN轴突寻路中的具体作用；3)研究Ctip2与其家族成员Ctipl在发育中的相互作用。这些研究将阐明Ctip2 （CSMN识别的中心调节因子）单独或与其他基因协同作用的机制，以指导这种临床上重要的神经元类型的发育。本研究具有重要的临床意义。由于CSMN是肌萎缩性侧索硬化症（ALS）中退化的大脑神经元，也是脊髓损伤中受损的中心群体，因此详细了解调节这一特定投射神经元群体产生和成熟的遗传控制程序对于基本了解大脑组织和功能以及潜在的未来ALS、脊髓损伤的细胞修复策略的发展都是重要的。以及影响CSMN的其他疾病。

DESCRIPTION (provided by applicant): The long-term goals of the proposed experiments are both to elucidate the neuron subtype-specific development of neocortical projection neuron circuitry and to repair diseased neocortical projection neurons. During the development of the mammalian telencephalon, spatially and temporally heterogeneous progenitor cells generate a rich variety of projection neuron subtypes. Although key molecular controls over regionalization of progenitors have been extensively characterized, the investigation of genes regulating projection neuron subtype identity acquisition in postmitotic neurons has only relatively recently begun. Recent work in the Macklis laboratory (Arietta et al., Neuron '05; Molyneaux et al., Neuron '05; Ozdinler and Macklis, Nature Neurosci. '06; Molyneaux et al.. Nature Rev. Neurosci. '07; Arietta et al., J. Neurosci., '08; Lai et al.. Neuron '08; Joshi et al., Neuron '08; Azim et al., '09, Srubeck Tomassy et al., '09), complemented and broadened by work from other investigators, has identified a combinatorial program of transcription factor controls over the specification and differentiation of cortical projection neurons from progenitor cells. One such transcription factor, COUP-TF interacting protein 2 (Ctip2) has been shown by our laboratory to be centrally important for the differentiation of both corticospinal motor neurons (CSMN) (and related subcerebral projection neurons) in the neocortex and medium-sized spiny neurons (MSN) in the striatum; however, the specific molecular differentiation programs executed by Ctip2 in these important neuron types is unknown. In this proposal, I outline a program of research designed to investigate the functions of Ctip2 in CSMN development. I propose to 1) identify the specific role(s) of Ctip2 in CSMN axon extension and fasciculation; 2) delineate the specific role(s) of Ctip2 in CSMN axon pathfinding; and 3) investigate a possible interaction between Ctip2 and its family member Ctipl in the developing cortex. These studies will elucidate the mechanisms by which Ctip2, a central regulator of CSMN identity, acts alone and in concert with other genes to instruct the development of this clinically important neuron type. The proposed research has significant clinical implications. As CSMN are the brain neurons that degenerate in amyotrophic lateral sclerosis (ALS), and a central population damaged in spinal cord injury, a detailed understanding of the program of genetic controls regulating the generation and maturation of this specific projection neuron population is important both for fundamental understanding of brain organization and function, and for the potential future development of cellular repair strategies for ALS, spinal cord injury, and other diseases affecting CSMN.