Fate specification of corticospinal neurons by cell autonomous signaling

细胞自主信号传导对皮质脊髓神经元的命运规范

• 批准号: 8323686
• 负责人: Paola Arlotta
• 金额: $ 12.39万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8323686
• 关键词: Address; Affect; Amyotrophic Lateral Sclerosis; Bioinformatics; Birth; Brain; Cells; Cerebral cortex; Cessation of life; Color; Corpus Callosum; DNA; Data; Decision Making; Development; Disease; Electroporation; Embryo; Event; Generations; Genes; Goals; Hereditary Spastic Paraplegia; Heterogeneity; Human; Individual; Injection of therapeutic agent; Injury; Internal Capsule; Investigation; Laboratories; Microarray Analysis; Molecular; Molecular Analysis; Motor Neuron Disease; Motor Neurons; Mus; Mutant Strains Mice; Natural regeneration; Neonatal; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurons; Paralysed; Pathway interactions; Phosphotransferases; Play; Pontine structure; Population; Primary Lateral Sclerosis; Process; Property; Proteins; Publishing; Reporting; Role; Sampling; Screening procedure; Series; Signal Transduction; Spinal Cord; Spinal cord injury; Staging; Testing; Therapeutic; Time; Tissues; Work; base; body system; clinically relevant; combinatorial; gain of function; in utero; in vivo; in vivo Model; injured; loss of function; molecular marker; motor neuron degeneration; motor neuron development; mutant; nestin protein; neuroblast; neuron development; novel; novel therapeutics; overexpression; postnatal; progenitor; promoter; public health relevance; receptor; research study; response; selective expression; transcription factor

DESCRIPTION (provided by applicant): The goal of this proposal is to determine the molecular signals that instruct the fate specification and the lineage-specific development of corticospinal motor neurons (CSMN). These neurons are a clinically relevant population that, in humans, selectively dies in neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS), Hereditary Spastic Paraplegia (HSP), and Primary Lateral Sclerosis (PLS). They are also the cells permanently injured and responsible for paralysis in spinal cord injury (SCI). In the nervous system, studies aimed at investigating the molecular controls over birth, survival and connectivity of individual neuron types have been notoriously difficult, owing to the astonishing cellular heterogeneity of the tissue, combined with the inability to distinguish and purify one neuron type in isolation from others. In my postdoctoral work, I addressed this issue directly in the cortex, and have identified and begun to functionally characterize the first series of genes that in a combinatorial fashion uniquely identify CSMN as this neuron type develops [1]. Most relevant to the present proposal, we discovered that the transcription factor Fezf2 is a "master gene" that is both necessary for the birth of CSMN (i.e. CSMN are absent from the cortex of Fezf2-/- mice), and is at least in part sufficient to instruct the fate-specification of cortical progenitors to CSMN (i.e. elevated levels of Fezf2 can induce a "fate-switch" in progenitors destined to form upper layer neurons towards forming CSMN and deep layer neurons) [2]. Here, I build on this prior work and on new data from my own laboratory to directly investigate the central questions of this proposal: (1): What are the molecular signals that instruct the fate-specification and early development of cortical progenitors into CSMN? (Aim 1 and Aim 2) (2): Do postmitotic neurons of a different cortical type maintain the ability to generate CSMN in response to Fezf2 or, rather, are neuron lineage-specification decisions made and only modulated at the progenitor stage? (Aim 3) We present prior published work and substantial new data that support the feasibility of these experiments, and the direct relevance of the results to the development of novel therapeutic strategies to replace CSMN in neurodegenerative and traumatic diseases of the corticospinal circuitry. PUBLIC HEALTH RELEVANCE: Different neurodegenerative diseases of the CNS are typically characterized by the progressive death of specific neuron types. Corticospinal motor neuron (CSMN) degeneration and injury is a key component of motor neuron disease (including ALS), and of spinal cord injury. Here we propose to determine the molecular signals that instruct the birth of this clinically relevant neuron type, and to investigate the extent to which CSMN can be regenerated for therapeutic application.

描述(由申请人提供)：本提案的目标是确定指导皮质脊髓运动神经元(CSMN)命运指定和谱系特异性发育的分子信号。这些神经元是临床上相关的群体，在人类中，它们选择性地死于神经退行性疾病，包括肌萎缩侧索硬化症(ALS)、遗传性痉挛截瘫(HSP)和原发性侧索硬化症(PLS)。它们也是永久性损伤的细胞，并对脊髓损伤(SCI)的瘫痪负责。在神经系统中，针对单个神经元类型的出生、存活和连接的分子控制的研究一直是出了名的困难，因为组织的细胞异质性令人震惊，而且无法将一种神经元类型与其他神经元类型隔离开来。在我的博士后工作中，我直接在大脑皮层解决了这个问题，并已经确定并开始描述第一系列基因的功能，这些基因以组合的方式唯一地识别CSMN作为这种神经元类型的发育[1]。与目前的建议最相关的是，我们发现转录因子Fezf2是CSMN诞生所必需的“主基因”(即CSMN在Fezf2-/-小鼠的皮质中缺失)，并且至少部分足以指示皮层祖细胞对CSMN的命运指定(即Fezf2水平的升高可以诱导注定要形成上层神经元的前体细胞向形成CSMN和深层神经元的“命运转换”)[2]。在这里，我在之前的工作和我自己实验室的新数据的基础上，直接研究这一提议的核心问题：(1)：什么是指导皮质前体细胞向CSMN的命运指定和早期发展的分子信号？(目标1和目标2)(2)：不同皮质类型的有丝分裂后神经元是否保持对Fezf2的反应而产生CSMN的能力，或者更确切地说，神经元谱系特征的决定是否做出并仅在祖细胞阶段进行调节？(目的3)我们介绍了先前发表的工作和大量新的数据，支持这些实验的可行性，以及结果与开发新的治疗策略的直接相关性，以取代皮质脊髓回路的神经退行性疾病和创伤性疾病。 公共卫生相关性：中枢神经系统的不同神经退行性疾病的典型特征是特定神经元类型的进行性死亡。皮质脊髓运动神经元(CSMN)变性损伤是运动神经元病(包括ALS)和脊髓损伤的重要组成部分。在这里，我们建议确定指导这种临床相关神经元类型诞生的分子信号，并调查CSMN再生用于治疗应用的程度。