Ctip2 Function in Corticospinal Motor Neuron Development

描述(申请人提供)：拟议实验的长期目标既是为了阐明新皮质投射神经元回路的神经元亚型特异性发育，也是为了修复患病的新皮质投射神经元。在哺乳动物端脑发育过程中，在空间和时间上异质性的前体细胞产生了丰富多样的投射神经元亚型。尽管对祖细胞区域化的关键分子控制已经被广泛地描述，但调控有丝分裂后神经元中投射神经元亚型获得的基因的研究才相对较晚。Macklis实验室最近的工作(Arietta等人，Neuron‘05；Molyneaux等人，Neuron’05；Ozdinler和Macklis，自然神经科学)。‘06；Molyneaux et al.自然牧师神经科学。‘07；Arietta et al.，J.Neurosci，’08；Lai等人.Neuron‘08；Joshi等人，Neuron’08；Azim等人，‘09，Srubeck Tomassy等人，’09)，通过其他研究人员的工作进行补充和扩展，已经确定了转录因子控制皮质投射神经元与祖细胞的指定和分化的组合程序。其中一种转录因子COUP-TF相互作用蛋白2(Ctip2)对新皮质的皮质脊髓运动神经元(CSMN)(及相关的脑下投射神经元)和纹状体中的中型棘神经元(MSN)的分化具有中枢作用；然而，Ctip2在这些重要神经元类型中执行的特定分子分化程序尚不清楚。在这个提案中，我概述了一个旨在研究Ctip2在CSMN发育中的功能的研究计划。我建议1)确定Ctip2在CSMN轴突延伸和分束中的特定作用(S)；2)描述Ctip2在CSMN轴突发现中的特定作用(S)；以及3)研究Ctip2与其家族成员Ctip1在发育皮质中的可能相互作用。这些研究将阐明Ctip2，CSMN特性的中央调节因子，通过单独和与其他基因协同作用来指导这种临床上重要的神经元类型的发育。这项拟议的研究具有重要的临床意义。由于CSMN是肌萎缩侧索硬化症(ALS)中变性的脑神经元，也是脊髓损伤中受损的中心群体，因此详细了解调控这一特定投射神经元群体的生成和成熟的遗传控制程序对于基本了解脑组织和功能以及未来针对ALS、脊髓损伤和其他影响CSMN的疾病的细胞修复策略的发展都是重要的。

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.