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（由申请人提供）：拟议的实验的长期目标都是旨在阐明对皮质脊髓运动神经元（CSMN）神经元亚型特异性发育（以及相关的新皮质投射神经元）的分子基因对照，并有潜在地启用了未来修复变性或受伤的CSMN的方法。 CSMN在所有新皮质投射神经元上都是开发原型的，并且在临床上是脑肌营养性侧面硬化症 /运动神经元疾病（ALS / MND）中脱生的脑神经元，其轴突损伤对于脊髓损伤的运动功能丧失至关重要。提出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相互作用蛋白2）及其旁系同源物CTIP1在鼠新皮层中CSMN和相关神经元开发中的功能。 CTIP2越来越多地成为CSMN发育和连通性的关键调节剂，也是通过多个投影神经元亚型分化途径的调控（在很大程度上抑制）的常见目标。从其他器官系统中知道CTIP2参与发展谱系规范决策。在新皮层中，CTIP2由CSMN和相关的脑投射神经元特别表达，对于出生，偶像和靶向CSMN轴突是必不可少的。尽管CTIP2对CSMN的发展非常重要，但其功能的大多数方面仍然未知。 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鉴定为关键的CSMN分子对照，并证明CTIP2 - / - 小鼠中的CSMN轴突在穿透内部胶囊（IC）（IC）之前被误处理，并在IC中缺乏，并且未能将其引向脊髓（SC）。由于CTIP2还控制了围绕IC中CSMN轴突的纹状体中型棘神经元（MSN）的分化，因此该假设被认为是CTIP2 - / - CSMN与SC中的某些缺陷可能是由于CTIP2 - // - / - MSN中轴突生长和指导控制的失调而导致的SC。仅在新皮层（EMX1-CRE; CTIP2FL/FL）中缺乏CTIP2的小鼠表明，CSMN的子集进入并在IC中引起了群体，有些甚至达到SC。其他初步研究发现，CTIP2旁系同源物CTIP1与CTIP2交叉相互作用以控制深层投影神经元的发育，并且CTIP1还调节了面积的组织。 拟议的实验将：（目标1，2）CTIP2在CSMN轴突生长和着迷中划定了CSMN自主和非CSMN自治作用； （目标3，4）研究新鉴定的遗传性交叉相互作用 CTIP2及其在CSMN开发中的旁系同源物CTIP1之间，以及CTIP1在Areal组织中的独立作用以及其他深层投影神经元的发展。该提案以外的实验可以通过CSMN中的CTIP2直接或间接识别基因。这些研究将阐明CTIP2（CSMN分化的中心调节剂）单独起作和其他基因的机制，以指导这种发育典型，临床上重要的神经元类型的发展。 公共卫生相关性：退化性和创伤性神经系统疾病是巨大的个人痛苦和残疾的根源，它们造成了巨大的公共卫生财务和社会负担；其中包括涉及涉及脑皮质“长连接”神经细胞的神经退行性疾病，称为“皮质脊髓运动神经元”（CSMN），例如ALS /“ Lou Gehrig的疾病”，原发性侧面硬化症（PLS），遗传性痉挛性Parappastic Parapleaplegia（hsp）和Huntington's（HD）;和创伤性脊髓损伤（SCI）。一个称为CTIP2的基因和分子越来越多地成为对CSMN的发展和功能的关键控制，并且是控制大脑发育和功能的中心途径的关键调节“中心”，但其功能的大多数方面仍然未知。基于最近确定对这些“脑皮质到脊髓”脑神经元的生长和功能的分子控制的工作，该项目将对CTIP2进行最新研究 这种重要的神经元类型在小鼠中的生长，健康和正确的功能，用于治疗损伤或退化神经元的新方法，在大脑中最高的大脑区域，与脊髓相关，与人类ALS，SCI，SCI，HSP，PLS相关的核心。