Molecular Control of Cortical Projection Neuron Identity and Connectivity

皮质投射神经元身份和连接性的分子控制

• 批准号: 8844122
• 负责人: NENAD SESTAN
• 金额: $ 8.33万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8844122
• 关键词: Autistic Disorder; Binding Sites; Brain; Brain Diseases; Brain region; Cells; Cerebral cortex; Cognitive; Complex; Corticospinal Tracts; Data; Defect; Development; Disease; Embryo; Embryonic Development; Enhancers; Event; Exhibits; FGFR1 gene; Foundations; Gene Expression; Genes; Goals; Grant; Health; Human; Impairment; Laboratories; Language; Mediating; Mental Retardation; Molecular; Molecular Genetics; Motor; Motor output; Mus; NOTCH1 gene; NRP1 gene; Neurobiology; Neurons; Output; Pattern; Positioning Attribute; Publishing; Regulation; Regulatory Element; Research; Role; Schizophrenia; Signal Transduction; Specific qualifier value; Synapses; System; Thalamic structure; axon guidance; behavior influence; cell type; design; gene function; hippocampal pyramidal neuron; migration; neocortical; neuron development; neurotrophic factor; neurotropin; novel therapeutics; progenitor; research study; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): The ability to accomplish and develop complex cognitive and motor tasks depends on the accuracy and intricacy of synaptic connections both within the cerebral cortex and between the cortex and other regions of the brain. Axonal projections of excitatory projection (pyramidal) neurons constitute the motor output of the entire cortex and directly influence behavior. Molecular mechanisms regulating the molecular identity and connectivity of distinct cortical projection neurons are being unraveled. Our goal is to identify mechanisms that are important for the migration, molecular identity and connectivity of pyramidal neurons, and to investigate their functional roles using a variety of molecular and genetic approaches. Our published and preliminary studies, supported by this grant in the last four years, have functionally characterized several genes encoding transcription factors and axon guidance that control different aspect of cortical projection neuron development, such as their molecular identity, laminar position, dendritic arborization, and axonal projections. In this application we intend to further characterize the cellular and molecular mechanisms by which some of these genes function. Specifically, the proposed experiments are designed to determine how Sox5 controls early-born subcortical projection neurons migration to their proper laminar positions and extend axonal projections (Aim1); how layer-specific expression of Fezf2 and subsequently the molecular identity of projection neurons are controlled cell-intrinsically by upstream transcriptional regulators (Aim2); and how formation of axonal connections with subcortical targets, such as the thalamus, controls gene expression cell-extrinsically in cortical projection neurons during late embryogenesis (Aim3).

描述（由申请人提供）：完成和发展复杂的认知和运动任务的能力取决于大脑皮层内部以及皮层与大脑其他区域之间突触连接的准确性和复杂性。兴奋性投射（锥体）神经元的轴突投射构成整个皮层的运动输出，并直接影响行为。调节不同皮质投射神经元的分子特性和连通性的分子机制正在被解开。我们的目标是确定对锥体神经元的迁移、分子身份和连通性重要的机制，并利用各种分子和遗传方法研究它们的功能作用。我们在过去四年中发表的和初步的研究，在这项资助的支持下，从功能上表征了几个基因编码转录因子和轴突引导，这些基因控制着皮层投射神经元发育的不同方面，如它们的分子身份、层流位置、树突树突和轴突投射。在这个应用程序中，我们打算进一步表征细胞和分子机制，其中一些基因的功能。具体来说，所提出的实验旨在确定Sox5如何控制早期出生的皮层下投射神经元向其适当的层状位置迁移并扩展轴突投射（Aim1）；Fezf2的层特异性表达以及随后投射神经元的分子特性如何受到上游转录调节因子（Aim2）的细胞内在控制；以及在胚胎发生后期，轴突与皮层下靶点（如丘脑）的连接如何在细胞外控制皮层投射神经元的基因表达（Aim3）。

项目成果

Neuroscience. The emerging biology of autism spectrum disorders.

• DOI: 10.1126/science.1224989
• 发表时间: 2012-09-14
• 期刊: Science (New York, N.Y.)
• 作者: State MW;Šestan N
• 通讯作者: Šestan N

Spatio-temporal transcriptome of the human brain.

• DOI: 10.1038/nature10523
• 发表时间: 2011-10-26
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Kang, Hyo Jung;Kawasawa, Yuka Imamura;Cheng, Feng;Zhu, Ying;Xu, Xuming;Li, Mingfeng;Sousa, Andre M. M.;Pletikos, Mihovil;Meyer, Kyle A.;Sedmak, Goran;Guennel, Tobias;Shin, Yurae;Johnson, Matthew B.;Krsnik, Zeljka;Mayer, Simone;Fertuzinhos, Sofia;Umlauf, Sheila;Lisgo, Steven N.;Vortmeyer, Alexander;Weinberger, Daniel R.;Mane, Shrikant;Hyde, Thomas M.;Huttner, Anita;Reimers, Mark;Kleinman, Joel E.;Sestan, Nenad
• 通讯作者: Sestan, Nenad

From trans to cis: transcriptional regulatory networks in neocortical development.

• DOI: 10.1016/j.tig.2014.12.004
• 发表时间: 2015-02
• 期刊: Trends in genetics : TIG
• 作者: Shibata M;Gulden FO;Sestan N
• 通讯作者: Sestan N

Cortical projection neurons: sprung from the same root.

• DOI: 10.1016/j.neuron.2013.11.016
• 发表时间: 2013-12-04
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Han W;Sestan N
• 通讯作者: Sestan N