Molecular development and diversity of callosal projection neurons

胼胝体投射神经元的分子发育和多样性

• 批准号: 9224046
• 负责人: JEFFREY D MACKLIS
• 金额: $ 42.38万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9224046
• 关键词: Area; Autistic Disorder; Axon; Behavior; Behavior Disorders; Behavioral; Brain; Cerebral cortex; Cerebral hemisphere; Cognition; Cognition Disorders; Cognitive; Complex; Corpus Callosum; Data; Dendrites; Development; Developmental Biology; Diagnosis; Diffusion Magnetic Resonance Imaging; Disease; Embryo; Evolution; Exhibits; Functional disorder; Future; Generations; Genes; Goals; Growth Cones; Health; Human; Imagery; Individual; Intellectual functioning disability; Investigation; Knowledge; Label; Link; Location; Mass Spectrum Analysis; Mental disorders; Molecular; Motor; Mus; Neocortex; Neurons; Phenotype; Plasmids; Play; Population; Population Analysis; Positioning Attribute; Preparation; Prevention; Process; Proteome; Proteomics; RNA; Research; Resolution; Schizophrenia; Sensory; Sensory Process; Specific qualifier value; Staging; Structure; Synapses; System; Technology; Therapeutic; Time; Work; autism spectrum disorder; axon growth; base; developmental disease; genetic manipulation; hippocampal pyramidal neuron; human disease; information processing; innovation; insight; interest; loss of function; neocortical; neuron development; neuronal cell body; neuronal circuitry; novel; overexpression; postnatal; prevent; progenitor; recombinase; research study; somatosensory; transcriptome sequencing; transcriptomics

 DESCRIPTION (provided by applicant): The long-term goals of the proposed research are both to elucidate central molecular controls over development and diversity of neocortical callosal projection neurons (CPN), and to identify potential causes and therapeutic approaches to disease involving CPN. CPN are the broad population of interhemispheric pyramidal neurons whose axons connect the two cerebral hemispheres via the corpus callosum. CPN play key roles in high-level associative, integrative, cognitive, behavioral, sensory, and motor functions, based on precise, area-specific CPN subtype connectivity and diversity. Disruptions in CPN development are correlated with deficits in multiple cognitive and behavioral disorders, including agenesis of the corpus callosum, autism spectrum disorders, and schizophrenia. Currently, how the remarkable diversity of CPN subtypes and connectivity is specified, and how they differentiate to form highly precise and specific circuits, is unknown. Our lab recently identifieda combinatorially-expressed set of genes that both define CPN as a broad population, and identify novel subpopulations of CPN during embryonic and early postnatal development (Arlotta, Neuron, 2005; Molyneaux, J Neurosci, 2009). Building on our previous work and substantial preliminary data, we propose deep and rigorous functional investigation of Cited2, one newly identified transcriptional co-regulator that we hypothesize functions importantly in development of areally- and functionally-specific subtypes of CPN, notably somatosensory CPN, and its dysfunction might contribute to disorders of CPN connectivity and diversity. We have completed quite substantial, highly motivating preliminary studies of Cited2 function in neocortical development, leading to the hypothesis that Cited2 regulates and refines two stages of precise CPN development and diversity, functioning 1) broadly in basal progenitors to regulate generation of superficial layer CPN, and 2) in an areally-restricted manner to refine distinct identity and development of somatosensory (S1) CPN. To further investigate this hypothesis, we propose to: Aim 1) investigate development and precision of Cited2-null CPN axonal targeting; Aim 2) identify potential postmitotic-specific function(s) of Cited2 that are distinct from Cited2 function in progenitors; Aim 3) investigate CPN-autonomy of Cited2 function during S1 CPN development and connectivity, via novel mosaic, recombinase-based genetic manipulation technology ("BEAM") for dual population analysis; and Aim 4) investigate growth cone RNA and proteomes of WT vs Cited2 cKO S1 CPN during axonal development via an entirely new and innovative approach, to gain direct mechanistic understanding of CPN circuit development. Together, these proposed studies will provide substantial insight into molecular controls over development and diversity of CPN subtypes with distinct connectivity, function, and integration of cortical information, processes centrally disrupted in multiple human disorders. Such controls over CPN diversity are currently essentially unknown. This research will contribute to understanding of cortical organization, function, evolution, and potentially toward prevention, diagnosis, and future therapy of human developmental disorders.

 描述（由申请人提供）：拟议研究的长期目标是阐明新皮质胼胝体投射神经元（CPN）发育和多样性的中心分子控制，并确定涉及 CPN 的疾病的潜在原因和治疗方法。是大脑半球间锥体神经元的广泛群体，其轴突通过胼胝体连接两个大脑半球，在高级联想、整合、 CPN 发育的破坏与多种认知和行为障碍的缺陷相关，包括胼胝体发育不全、自闭症谱系障碍等。目前，我们的实验室最近发现了一组组合表达的基因，这些基因是如何指定 CPN 亚型和连接性的，以及它们如何分化形成高度精确和特定的电路的。将 CPN 定义为一个广泛的群体，并在胚胎和出生后早期发育期间识别 CPN 的新亚群（Arlotta，Neuron，2005；Molyneaux，J Neurosci，2009）基于我们之前的工作和大量初步数据，我们提出了深入而严格的功能。对 Cited2 的研究，这是一种新发现的转录共调节因子，我们参与了 CPN 区域和功能特异性亚型（特别是体感亚型）发展中的重要功能CPN 及其可能导致 CPN 连接性和多样性障碍。我们已经完成了对 Cited2 在新皮质发育中的功能的相当实质性、高度激励性的初步研究，从而得出这样的假设：Cited2 调节和完善了精确的 CPN 发育和多样性、功能的两个阶段。 1) 广泛地在基底祖细胞中调节浅层 CPN 的生成，2) 以区域限制的方式细化体感 (S1) CPN 的独特身份和发育，以进一步研究。根据这一假设，我们提出：目标 1) Cited2 无效 CPN 轴突靶向的开发和精确度；目标 2) 识别与祖细胞中 Cited2 功能不同的潜在的有丝分裂后特异性功能；目标 3) 研究 CPN -通过新颖的嵌合、基于重组酶的基因操作技术（“BEAM”）进行双群体分析，在 S1 CPN 发育和连接过程中保持 Cited2 功能的自主性；目标 4) 通过全新的创新方法在轴突发育过程中比较 WT 与 Cited2 cKO S1 CPN 的生长锥 RNA 和蛋白质组，以获得对 CPN 回路发育的直接机制理解，这些拟议的研究将为发育的分子控制提供深入的见解。具有不同连接性、功能和皮质信息整合的 CPN 亚型的多样性，这种对 CPN 多样性的控制目前基本上是未知的。皮质组织、功能、进化，以及人类发育障碍的预防、诊断和未来治疗的潜力。