Foxp-regulated signaling pathways in brain development - Diversity

大脑发育中 Foxp 调节的信号通路 - 多样性

• 批准号: 10478320
• 负责人: Genevieve Konopka
• 金额: $ 8.02万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478320
• 关键词: Automobile Driving; Behavior; Behavioral; Biological Models; Brain; Brain Diseases; Cell Nucleus; Cells; Cerebral cortex; Childhood; Chromatin; Corpus striatum structure; Coupling; Data; Development; Electrophysiology (science); Etiology; FOXP1 gene; FOXP2 gene; Family; Funding; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Heritability; Impairment; Intellectual functioning disability; Journals; Language Disorders; Link; Mental disorders; Mission; Molecular; Mus; National Institute of Mental Health; Nature; Neurodevelopmental Disorder; Neurons; Neurosciences; Phenotype; Physiology; Publishing; Regulator Genes; Research; Research Training; Resolution; Risk; Rodent Model; Role; Signal Pathway; Signal Transduction; Small Nuclear RNA; Speech; Technology; Time; Training; Variant; Work; XCL1 gene; autism spectrum disorder; base; cell type; experimental study; genomic data; insight; member; migration; neurogenomics; neuropsychiatric disorder; parent grant; programs; single-cell RNA sequencing; skills; targeted treatment; transcription factor; transcriptome sequencing

RESEARCH AND TRAINING PLAN FOR RACHAEL VOLLMER A. SUMMARY OF THE FUNDED GRANT The parent grant (R01MH126481; funding period 06/01/21-05/31/2026) is titled: “Foxp-regulated signaling pathways in 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 the work in the parent grant and the proposed supplement 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 two specific aims that will utilize snATAC- seq: 1) Determine the cell type-specific gene regulatory programs orchestrated by Foxp1 in the developing cortex; and 2) Determine the cell type-specific gene regulatory programs orchestrated by Foxp2 in the developing cortex. 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 provide insight into the basic molecular mechanisms governing normal mammalian brain development. These research aims support the mission of the NIMH to understand and develop treatments for mental disorders. Finally, the training plan that we have described in this proposal will provide Ms. Vollmer with a cutting-edge skill set in neurogenomics. Aims 1 and 2 of the parent grant are to identify the cell-type specific developmental transcriptional program regulated by Foxp1 or Foxp2 in the mouse brain using single-nuclei RNA-sequencing (snRNA-seq) at several time points. These experiments will utilize previously generated Foxp1 and Foxp2 cKO mice already generated and published using Emx1.Cre (e.g. Araujo et al., Journal of Neuroscience 2017; Usui et al., Genes & Development 2017; Co et al., Cerebral Cortex 2020). Our lab has also recently applied the approach of single- nuclei ATAC-sequencing to uncover the cell type specific contributions of gene regulation and signaling cascades (e.g. Berto et al., Nature Neuroscience 2021). Coupling this chromatin accessibility approach with gene expression at the cell type level, should provide a new level of resolution for understanding how these transcription factors organize developmental signaling cascades. As described below, Rachael Vollmer will advance the aims of the parent grant by using the same Foxp1 and Foxp2 cKO mice proposed for snRNA-seq; however, she will apply snATAC-seq at the same timepoints to understand chromatin accessibility. This cell- specific approach will allow us to narrow down the direct transcriptional targets of Foxp1 and Foxp2 driving the observed phenotypes in these model systems such as impaired cortical migration and behavioral inflexibility.

Rachael Vollmer的研究与培训计划 A.资助赠款的摘要 父母赠款（R01MH126481；资金期限06/01/21-05/31/2026）的标题为：“ FOXP调节的信号 大脑发育中的途径。 已经与智力障碍，自闭症谱系障碍和特定语音的单基因形式有关 语言定义。 FOXP1或FOXP2中的变体是与 自闭症谱系障碍。我们以前表明FOXP1和FOXP2都有重大贡献 皮质和纹状体发育。我们通过研究基因表达，将这些发育变化联系起来 电生理学和行为。我们使用使用 新的单细胞RNA测序技术。基于这些数据，中心假设推动了 在父母赠款和拟议的补充中的工作是FOXP1和FOXP2是 转录信号传导以细胞类型特异性方式级联反应，对神经元功能很重要，并且是 神经发育障碍（例如自闭症）的风险。我们建议识别这些细胞类型特异性 通过使用啮齿动物模型通过两个特定目的使用啮齿动物的贡献，这些目标将利用SNATAC- SEQ：1）确定FOXP1在发育中策划的细胞类型特异性基因调节程序 皮质； 2）确定FOXP2在发育中精心策划的细胞类型特异性基因调节程序 皮质。这些目标在一起将描述FOXP1和FOXP2对皮质的细胞类型贡献 发展。啮齿动物模型和细胞类型特异性基因组数据集将提供有关基本的洞察力 分子机制管理正常的哺乳动物脑发育。这些研究的目的支持 NIMH的使命是了解和发展精神障碍的治疗方法。最后，培训计划 我们在该提案中描述了Vollmer女士在神经基因组学方面设置的尖端技能。 父母赠款的目标1和2是确定细胞类型的特定发育转录程序 使用单核RNA测序（SnRNA-Seq）在小鼠脑中由FOXP1或FOXP2调节 时间点。这些实验将利用先前生成的FOXP1和FOXP2 CKO小鼠已经生成 并使用emx1.cre出版（例如Araujo等，《神经科学杂志》，2017年； Usui等人，基因＆ 开发2017; Co等人，脑皮质2020）。我们的实验室最近还采用了单一的方法 核核酸核，以发现基因调节和信号传导的细胞类型特异性贡献 级联（例如Berto等人，自然神经科学2021）。将这种染色质访问方法与 基因表达在细胞类型水平上应提供新的分辨率，以理解这些水平 转录因子组织了开发信号级联。如下所述，Rachael Vollmer将 通过使用针对SnRNA-Seq提出的相同的FOXP1和FOXP2 CKO小鼠来提高父授予的目标； 但是，她将在同一时间点应用SNATAC-SEQ以了解染色质的可及性。这个细胞 - 具体方法将使我们能够缩小FOXP1和FOXP2的直接转录目标 在这些模型系统中观察到的表型，例如皮质迁移受损和行为僵化。