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: 8372817
• 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 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8372817
• 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

DESCRIPTION (provided by applicant): 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 projec 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. PUBLIC HEALTH RELEVANCE: Degenerative and traumatic neurological disorders are the source of great personal suffering and disability, and they account for a huge public health financial and social burden; these include neurodegenerative diseases involving cerebral cortex "long-connection" nerve cells termed "corticospinal motor neurons" (CSMN), such as ALS / "Lou Gehrig's disease", primary lateral sclerosis (PLS), hereditary spastic paraplegia (HSP), and Huntington's disease (HD); and traumatic spinal cord injury (SCI). A gene and molecule called Ctip2 has increasingly emerged as both a critical control over development and function of CSMN, and as a key regulatory "hub" for central pathways controlling brain development and function more generally, but most aspects of its function remain unknown. Building on recent work identifying molecular controls over these "cerebral cortex-to-spinal cord" brain neurons' growth and function, this project will pursue state-of-the-art investigation of how Ctip2 regulates the growth, health, and correct function of this important neuron type in mice, toward new approaches for the treatment of injured or degenerating neurons in the cerebral cortex, the highest region of the brain, that connect to the spinal cord and are central to human ALS, SCI, HSP, PLS.

描述(申请人提供)：拟议实验的长期目标是阐明对皮质脊髓运动神经元(CSMN)(以及相关的新皮质投射神经元)神经元亚型特异性发育的分子遗传学控制，并潜在地使未来修复退化或受损CSMN的方法成为可能。CSMN既是所有新皮质投射神经元的发育原型，也是肌萎缩侧索硬化症/运动神经元病(ALS/MND)中变性的脑神经元，其轴突损伤是脊髓损伤中运动功能丧失的中心。拟议的实验将深入研究中枢重要的CSMN/脑下特异性转录因子CTIP2(COUP-TF相互作用蛋白2)及其同源CTIP1在CSMN及其相关神经元在小鼠新皮质发育中的功能。Ctip2已经逐渐成为CSMN发育和连接的关键调节因子，并成为多个投射神经元亚型分化通路调节(主要是抑制)的共同靶点。从其他器官系统中已知Ctip2参与了发育谱系的决定。在新皮质内，CTIP2由CSMN和相关的脑下投射神经元特异性表达，是CSMN轴突生长、聚集和靶向所必需的。虽然Ctip2已经成为CSMN发育的核心重要因素，但其大部分功能仍不清楚。大量的初步数据支持这些目标。本实验室以前的工作确定Ctip2是关键的CSMN分子控制因素，并证明Ctip2/-小鼠的CSMN轴突在穿过内囊(IC)之前被错误地发送，在IC内脱束，并未能投射到脊髓(SC)。由于CTIP2还控制着纹状体中等大小的棘神经元(MSN)的分化，Ctip2-/-CSMN与SC的连接可能是由于Ctip2-/-MSN的轴突生长和导向控制的失调所致。仅在新皮质缺乏Ctip2的小鼠(Emx1-Cre；Ctip2fl/fl)显示CSMN的一部分进入IC并成束，有些甚至到达SC。其他的初步研究发现，Ctip2与Ctip2相互作用，控制深层投射神经元的发育，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自主的Ctip2在CSMN轴突生长和丛生中的作用；(目标3，4)调查新发现的遗传交叉抑制相互作用 Ctip2和Ctip1在CSMN发育中的相互作用，以及Ctip1在其他深层投射神经元的区域组织和发育中的独立作用。超出这一建议的实验可以识别CSMN中由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，单独和其他基因共同作用的机制，以指导这种发育原型、临床重要的神经元类型的精确发育。 与公共卫生相关：退行性和创伤性神经疾病是巨大的个人痛苦和残疾的来源，它们造成了巨大的公共卫生经济和社会负担；这些疾病包括涉及大脑皮层的神经退行性疾病，称为“皮质脊髓运动神经元”(CSMN)，如肌萎缩侧索硬化症/“Lou Gehrig病”、原发性侧索硬化症(PLS)、遗传性痉挛截瘫(HSP)和亨廷顿病(HD)；以及创伤性脊髓损伤(SCI)。一种名为Ctip2的基因和分子越来越多地成为CSMN发育和功能的关键控制因素，以及更广泛地控制大脑发育和功能的中央通路的关键调控“枢纽”，但其功能的大部分方面仍不清楚。在最近确定分子控制这些“大脑皮层到脊髓”脑神经元生长和功能的工作的基础上，这个项目将对Ctip2如何调控进行最先进的研究 这一重要的神经元类型在小鼠中的生长、健康和正确的功能，朝着治疗大脑皮质中受损或退化的神经元的新方法发展，大脑皮层是大脑的最高区域，连接到脊髓，是人类ALS、SCI、HSP、PLS的中枢。