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: 8998073
• 负责人: JEFFREY D MACKLIS
• 金额: $ 36.97万
• 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 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8998073
• 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; 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; axon injury; 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. 项目概要/摘要 拟议实验的长期目标是阐明分子遗传控制 皮质脊髓运动神经元（CSMN）（以及相关的新皮质神经元）的神经元亚型特异性发育 投射神经元），并有可能使未来能够修复退化或受损的 CSMN。 CSMN 是所有新皮质投射神经元的发育原型，并且在临床上很重要 肌萎缩侧索硬化症/运动神经元病 (ALS/MND) 中退化的脑神经元 其轴突损伤是脊髓损伤中运动功能丧失的核心。所提出的实验将深入 研究中心重要的 CSMN/大脑下特异性转录因子 CTIP2 (COUP-TF 相互作用蛋白 2) 及其旁系同源物 CTIP1 在小鼠新皮质 CSMN 和相关神经元发育中的作用。 Ctip2 日益成为 CSMN 发展和连接的关键调节因子， 作为多投射神经元亚型分化调节（主要是抑制）的共同目标 途径。已知其他器官系统中的 Ctip2 参与发育谱系规范 决定。在新皮质内，CTIP2 由 CSMN 和相关的脑下投射特异性表达 神经元，并且对于 CSMN 轴突的生长、束颤和靶向是必需的。虽然 Ctip2 有 尽管它对于 CSMN 的发展至关重要，但其功能的大部分方面仍然未知。 大量初步数据支持这些目标。该实验室之前的工作将 Ctip2 确定为 关键的 CSMN 分子控制，并证明 Ctip2-/- 小鼠中的 CSMN 轴突在 穿透内囊 (IC)，在 IC 中解束，并且无法投射到脊髓 (SC)。 因为 CTIP2 还控制纹状体中型多棘神经元 (MSN) 的分化，该神经元围绕 IC 中的 CSMN 轴突，假设 Ctip2-/- CSMN 与 SC 的连接存在一些缺陷 可能是由于 Ctip2-/- MSN 中轴突生长和引导控制失调所致。仅缺乏 Ctip2 的小鼠 在新皮质 (Emx1-Cre;Ctip2fl/fl) 中，CSMN 的一个子集进入 IC 并在 IC 中成束，有些甚至 到达 SC。其他初步研究发现 Ctip2 旁系同源物 Ctip1 与 Ctip2 存在交叉抑制相互作用 控制深层投射神经元发育，并且 Ctip1 还调节区域组织。 拟议的实验将：（目标 1、2）描绘 CSMN 自主和非 CSMN 自主角色 Ctip2 在 CSMN 轴突生长和束化中的作用； （目标 3、4）调查新发现的基因交叉 Ctip2 及其旁系同源物 Ctip1 在 CSMN 发育中的抑制性相互作用以及独立作用 Ctip1 在区域组织和其他深层投射神经元发育中的作用。实验超越 该提议可以鉴定CSMN中Ctip2直接或间接调控的基因。这些研究将阐明 Ctip2（CSMN 分化的中央调节因子）单独或与其他基因一起作用的机制 指导这种发育原型、临床上重要的神经元类型的发育精度。