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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：拟议的研究的长期目标既阐明了中央分子控制对新皮质呼叫的投射神经元（CPN）的发育和多样性的控制，并确定了涉及CPN的疾病的潜在原因和治疗方法。 CPN是庞大的半球锥体神经元，其轴突通过call体连接两个脑半球。 CPN基于精确，特定于区域的CPN子类型的连接性和多样性，在高级关联，集成，认知，行为，感觉和运动功能中扮演关键角色。 CPN发育中的破坏与多种认知和行为障碍的缺陷有关，包括callosum callosum，自闭症谱系障碍和精神分裂症。当前，如何指定CPN亚型和连接性的显着多样性，以及它们如何区分形成高度精确和特定的电路。我们的实验室最近确定了将CPN定义为广泛人群的组合表达的基因组，并确定了胚胎和早期产后发育过程中CPN的新型亚群（Arlotta，Neuron，2005; Molyneaux，J Neurosci，JNeurosci，2009年）。 Building on our previous work and substantial preliminary data, we propose deep and rigorous functional investment of Cited2, one newly identified transcriptional co-regulator that we hypothesize functions importantly in development of all- and functionally-specific subtypes of CPN, notably somatosensory CPN, and its dysfunction might contribute to disorders of CPN connectivity and diversity.我们已经完成了对新皮质发展中引用的2功能的实质性，高度动机的初步研究，导致假说2引用2调节和完善了精确的CPN发育和多样性的两个阶段，1）在基本祖细胞中广泛起作用，以调节表面层的CPN的产生，以及在差异的方式中，以降低了差异的方式和2），以降低了差异的态度和发展。为了进一步研究这一假设，我们提出：目标1）研究引用的2-null CPN轴突靶向的发育和精度； AIM 2）确定与祖细胞中cusit2功能不同的cucit2的潜在有丝分裂后特异性功能；目标3）通过新型的基于重组酶的基因操纵技术（“ Beam”）进行双重人群分析，研究了S1 CPN发展和连通性期间CPN Autonomy的CPN自治；目标4）通过一种全新的创新方法研究轴突开发过程中WT与WT引用的2 CKO S1 CPN的生长锥RNA和蛋白质组织，以获得对CPN电路发展的直接机械理解。总之，这些提出的研究将提供对CPN亚型的发育和多样性的分子控制，具有独特的连通性，功能和皮质信息的整合，这些过程中集中破坏了多种人类疾病。目前，对CPN多样性的这种控制基本未知。这项研究将有助于理解皮质组织，功能，进化，并有可能对人类发育障碍的预防，诊断和未来治疗。