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Foxp-regulated signaling pathways in brain development

大脑发育中 Foxp 调节的信号通路

基本信息

批准号：
10315542
负责人：
Genevieve Konopka
金额：
$ 64.31万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10315542
关键词：
Acute Affect Anatomy Automobile Driving Behavior Behavioral Biological Assay Brain Brain Diseases Bromodeoxyuridine Cell Nucleus Cell physiology Cells Childhood Corpus striatum structure Data Development Disease Dopamine Receptor Electrophysiology (science)Electroporation Embryo Loss Etiology FOXP1 gene FOXP2 gene Family Financial compensation Gene Expression Genes Genetic Transcription Goals Heritability Individual Injections Intellectual functioning disability Interneurons Knockout Mice Laboratories Language Disorders Link Measurement Molecular Mutation Neocortex Neurodevelopmental Disorder Neurons Normal Cell Ontology Pathway interactions Phenotype Physiology Proteins Publications Publishing RNA analysis Recurrence Reversal Learning Risk Rodent Model Role Signal Pathway Signal Transduction Slice Small Nuclear RNA Speech Synaptic Transmission Tamoxifen Technology Testing Thick Time Tissue Harvesting Variant Work autism spectrum disorder base behavioral phenotyping cell type conditional knockout de novo mutation developmental disease experimental study functional genomics functional outcomes genomic data in utero insight member migration neocortical neuronal excitability neuropsychiatric disorder postnatal progenitor programs risk variant single-cell RNA sequencing social synaptic function targeted treatment transcription factor transcriptome sequencing

项目摘要

Project Summary/Abstract The contribution of individual disease-relevant genes to brain development still remains unknown. The long-term goal of our laboratory is to elucidate the intersection of molecular signaling pathways that are disrupted in neurodevelopmental disorders with those pathways that are important for specific aspects of brain development. Two members of the FOXP family of transcription factors, FOXP1 and FOXP2, have been linked to monogenetic forms of intellectual disability, autism spectrum disorders, and specific speech and language deficits. Variants in FOXP1 or FOXP2 are among the most significant genes associated with autism spectrum disorders. We previously showed that Foxp1 and Foxp2 both have significant contributions to cortical and striatal development. We linked these developmental changes via studies of gene expression, electrophysiology, and behaviors. We further identified non-cell-autonomous changes in gene expression using newly available single-cell RNA- sequencing technology. Based on these data, the central hypothesis driving this proposal is that Foxp1 and Foxp2 are key orchestrators of transcriptional signaling cascades in a cell type-specific manner that are important for neuronal function and are at risk in neurodevelopmental disorders such as autism. We propose to identify these cell type-specific contributions in the developing cortex by using rodent models through three specific aims: 1) Determine the cell type-specific gene expression programs regulated by Foxp1 in the developing cortex; 2) Determine the cell type-specific gene expression programs regulated by Foxp2 in the developing cortex; and 3) Assess the role of Foxp1 and Foxp2 in cell type-specific activity-dependent neuronal function. Together, these aims will delineate the cell type contribution of both Foxp1 and Foxp2 to cortical development. The rodent models and cell-type specific genomic datasets will aprovide insight into the basic molecular mechanisms governing normal mammalian brain development.

项目总结/摘要个体疾病相关基因对大脑发育的贡献仍然未知。长期我们实验室的目标是阐明分子信号通路的交叉点，神经发育障碍与那些对大脑发育的特定方面很重要的通路有关。转录因子FOXP家族的两个成员FOXP 1和FOXP 2已经与单基因遗传性各种形式的智力残疾、自闭症谱系障碍以及特定的言语和语言缺陷。中的变体 FOXP 1或FOXP 2是与自闭症谱系障碍相关的最重要的基因之一。我们先前的研究表明，Foxp 1和Foxp 2都对皮质和纹状体发育有重要贡献。我们通过对基因表达、电生理学和行为的研究将这些发育变化联系起来。我们使用新获得的单细胞RNA进一步鉴定了基因表达的非细胞自主变化，测序技术基于这些数据，推动这一提议的核心假设是Foxp 1 和Foxp 2是以细胞类型特异性方式的转录信号级联的关键协调，对神经元功能很重要，并且在神经发育障碍如自闭症中有风险。我们我建议通过使用啮齿动物模型来识别发育中皮层中这些细胞类型特异性的贡献，三个具体目标：1）确定Foxp 1在细胞中调控的细胞类型特异性基因表达程序， 2）确定Foxp 2调控的细胞类型特异性基因表达程序; 3）评估Foxp 1和Foxp 2在细胞类型特异性活动依赖性神经元细胞凋亡中的作用。功能总之，这些目标将描绘Foxp 1和Foxp 2对皮质神经元的细胞类型贡献。发展啮齿类动物模型和细胞类型特异性基因组数据集将提供对基本的控制正常哺乳动物大脑发育的分子机制。