Ctip2 Function in Corticospinal Motor Neuron Development

描述（由申请人提供）：所提出的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患病的新皮层投射神经元。在哺乳动物端脑的发育过程中，空间和时间异质的祖细胞产生了丰富多样的投射神经元亚型。虽然区域化的祖细胞的关键分子控制已被广泛的特点，有丝分裂后的神经元中的投射神经元亚型身份收购的基因调控的调查只是最近才开始。Macklis实验室最近的工作（Arietta等人，Neuron '05; Molyneaux等人，Neuron '05; Ozdinler和Macklis，Nature Neurosci. '06; Molyneaux等人。Nature Rev. Neurosci. '07; Arietta等人，神经科学杂志，'08; Lai et al. Neuron '08; Joshi等人，Neuron '08; Azim等人，'09，Srubeck Tomassy等人，09），通过其他研究者的工作补充和扩展，已经确定了转录因子控制来自祖细胞的皮质投射神经元的特化和分化的组合程序。 一个这样的转录因子，COUP-TF相互作用蛋白2（Ctip 2）已被我们的实验室证明是中央重要的分化皮质脊髓运动神经元（CSMN）（和相关的大脑下投射神经元）在新皮层和中型棘神经元（MSN）在纹状体，然而，具体的分子分化程序执行Ctip 2在这些重要的神经元类型是未知的。在这个建议中，我概述了一个研究计划，旨在调查Ctip2在CSMN开发中的功能。我建议1）鉴定Ctip 2在CSMN轴突延伸和成束中的特定作用; 2）描绘Ctip 2在CSMN轴突寻路中的特定作用;和3）研究Ctip 2和其家族成员Ctipl在发育皮层中的可能相互作用。这些研究将阐明Ctip 2（CSMN身份的中央调节因子）单独或与其他基因协同作用以指导这种临床重要神经元类型发育的机制。 这项研究具有重要的临床意义。由于CSMN是在肌萎缩侧索硬化症（ALS）中退化的脑神经元，并且是在脊髓损伤中受损的中央群体，因此详细了解调节该特定投射神经元群体的产生和成熟的遗传控制程序对于基本了解脑组织和功能以及ALS的细胞修复策略的潜在未来发展都是重要的。脊髓损伤和其他影响CSMN的疾病。

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.