Molecular Mechanisms of CTIP2 Function in Corticospinal Motor Neuron Development

CTIP2在皮质脊髓运动神经元发育中功能的分子机制

• 批准号: 8606666
• 负责人: JEFFREY D MACKLIS
• 金额: $ 36.6万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606666
• 关键词: Accounting; Amyotrophic Lateral Sclerosis; Area; Axon; Brain; Brain region; Cerebral cortex; Corpus striatum structure; Data; Defect; Development; Future; Genes; Genetic; Goals; Growth; Health; Hereditary Spastic Paraplegia; Human; Huntington Disease; Injury; Internal Capsule; Investigation; Laboratories; Molecular; Molecular Genetics; Motor; Motor Neurons; Mus; Muscle fasciculation; Neocortex; Neurodegenerative Disorders; Neurons; Pathway interactions; Primary Lateral Sclerosis; Proteins; Public Health; Regulation; Repression; Role; Sensory; Source; Spinal Cord; Spinal cord injury; Testing; Work; axon growth; axon guidance; body system; chicken ovalbumin upstream promoter-transcription factor; disability; injured; mind control; motor neuron development; neocortical; nerve supply; nervous system disorder; neuron development; novel; novel strategies; paralogous gene; programs; repaired; research study; social; transcription factor

7. PROJECT SUMMARY / ABSTRACT The long-term goals of the proposed experiments are both to elucidate molecular-genetic controls over the neuron subtype-specific development of corticospinal motor neurons (CSMN) (and related neocortical projection neurons), and to potentially enable future approaches to repair of degenerating or injured CSMN. CSMN are both developmentally prototypical for all neocortical projection neurons, and clinically important as the brain neurons that degenerate in amyotrophic lateral sclerosis / motor neuron disease (ALS/MND) and whose axonal injury is central to loss of motor function in spinal cord injury. Proposed experiments will deeply investigate function of the centrally important CSMN/subcerebral-specific transcription factor CTIP2 (COUP-TF interacting protein 2) and its paralog CTIP1 in development of CSMN and related neurons in murine neocortex. Ctip2 has increasingly emerged as both a critical regulator of development and connectivity of CSMN, and as a common target for regulation (largely repression) by multiple projection neuron subtype differentiation pathways. Ctip2 is known from other organ systems to be involved in developmental lineage specification decisions. Within the neocortex, CTIP2 is specifically expressed by CSMN and related subcerebral projection neurons, and is necessary for outgrowth, fasciculation, and targeting of CSMN axons. While Ctip2 has emerged as centrally important for CSMN development, most aspects of its function remain unknown. Substantial preliminary data support these aims. Previous work from this laboratory identified Ctip2 as a critical CSMN molecular control, and demonstrated that CSMN axons in Ctip2-/- mice are misrouted before penetrating the internal capsule (IC), defasciculate in the IC, and fail to project to the spinal cord (SC). Because CTIP2 also controls differentiation of striatal medium-sized spiny neurons (MSN), which surround CSMN axons in the IC, the hypothesis is suggested that some defects in Ctip2-/- CSMN connectivity to SC might result from dysregulation of axon growth and guidance controls in Ctip2-/- MSN. Mice lacking Ctip2 only in neocortex (Emx1-Cre;Ctip2fl/fl) reveal that a subset of CSMN enter and fasciculate in the IC, and some even reach the SC. Other preliminary studies find that the Ctip2 paralog Ctip1 interacts cross-repressively with Ctip2 to control deep-layer projection neuron development, and that Ctip1 additionally regulates areal organization. Proposed experiments will: (Aims 1, 2) delineate CSMN-autonomous and non-CSMN-autonomous roles of Ctip2 in CSMN axon growth and fasciculation; (Aims 3, 4) investigate a newly-identified genetically cross- repressive interaction between Ctip2 and its paralog Ctip1 in CSMN development, as well as independent roles of Ctip1 in areal organization and development of other deep-layer projection neurons. Experiments beyond this proposal could identify genes regulated directly or indirectly by Ctip2 in CSMN. These studies will elucidate mechanisms by which Ctip2, a central regulator of CSMN differentiation, acts alone and with other genes to instruct the precision of development of this developmentally prototypical, clinically important neuron type.

7。项目摘要 /摘要 提出的实验的长期目标都是阐明了分子遗传对手的控制 皮质脊髓运动神经元（CSMN）的神经元亚型特异性发育（及相关的新皮质 投射神经元），并有可能使未来的方法修复退化或受伤的CSMN。 CSMN在所有新皮质投射神经元上都是开发型的，临床上很重要 肌萎缩性侧性硬化症 /运动神经元疾病（ALS / MND）和 其轴突损伤是脊髓损伤中运动功能丧失的核心。建议的实验将深入 研究中心重要的CSMN/脑部特异性转录因子CTIP2（COUP-TF）的功能 相互作用的蛋白2）及其在鼠新皮层中CSMN和相关神经元发展的旁系同源物CTIP1。 CTIP2越来越多地成为CSMN发展和连通性的关键调节剂，而是 作为多个投影神经元亚型分化的调节的常见目标（在很大程度上抑制） 途径。从其他器官系统中知道CTIP2参与发育谱系规范 决定。在新皮层中，CTIP2由CSMN和相关的脑投射特别表达 神经元，对于CSMN轴突的出生，偶像和靶向是必要的。而CTIP2有 对于CSMN的发展而言，其功能的大多数方面仍然是不明的。 实质性的初步数据支持这些目标。该实验室的先前工作将CTIP2确定为 临界CSMN分子对照，并证明CTIP2 - / - 小鼠中的CSMN轴突在 穿透内部胶囊（IC），在IC中降级，无法投射到脊髓（SC）。 因为CTIP2还控制着围绕的纹状体中型棘神经元（MSN）的分化 IC中的CSMN轴突建议假设CTIP2 - / - CSMN连接到SC中的某些缺陷 可能是由于CTIP2 - / - MSN中轴突生长和引导控制的失调而引起的。仅缺少CTIP2的小鼠 在NeoCortex（EMX1-CRE; CTIP2FL/FL）中表明，CSMN的子集进入并在IC中出现，有些甚至是 到达SC。其他初步研究发现，CTIP2旁系同源物CTIP1与CTIP2交叉相互作用 控制深层投影神经元的发展，并且CTIP1还调节了面积的组织。 拟议的实验将：（目标1，2）描述CSMN自主和非CSMN自治角色 CSMN轴突的生长和迷信中的CTIP2； （目标3，4）研究一个新鉴定的遗传交叉 CTIP2及其旁系同源物CTIP1之间的抑制作用在CSMN开发中以及独立角色 CTIP1在各个深层投影神经元的组织中的开发和开发。实验之外 该建议可以通过CSMN中的CTIP2直接或间接地识别基因。这些研究将阐明 CTIP2是CSMN分化的中心调节剂，单独起作用的机制，与其他基因起作用 指导这种发育原型，临床上重要的神经元类型的开发精确度。