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.

瑞秋·沃尔默的研究和培训计划 A.资助赠款汇总表 母基金(R01MH126481；资助期06/01/21-05/31/2026)的标题为：FoxP调节的信号 大脑发育的途径。“FOXP转录因子家族的两个成员，Foxp1和FOXP2， 与单基因形式的智力残疾、自闭症谱系障碍和特定语言有关 和语言缺陷。Foxp1或FOXP2的变异是与 自闭症谱系障碍。我们之前已经证明，Foxp1和Foxp2都对 皮质和纹状体发育。我们通过对基因表达的研究将这些发育变化联系起来， 电生理学和行为。我们进一步确定了基因表达的非细胞自主变化 最新可用的单细胞RNA测序技术。基于这些数据，推动经济增长的核心假说 在父母拨款和拟议的补充中的工作是，Foxp1和Foxp2是 转录信号以特定细胞类型的方式级联，这对神经元功能很重要，并且 有患自闭症等神经发育障碍的风险。我们建议识别这些特定类型的细胞 通过利用SNATAC的两个特定目的使用啮齿动物模型在发育中的皮质中的贡献- SEQ：1)确定Foxp1在发育过程中编排的细胞类型特异性基因调控程序 以及2)确定Foxp2在发育过程中编排的细胞类型特异性基因调控程序 大脑皮层。总之，这些目标将描绘Foxp1和Foxp2对皮质的细胞类型贡献 发展。啮齿动物模型和特定细胞类型的基因组数据集将提供对基本 控制正常哺乳动物大脑发育的分子机制。这些研究目的支持 NIMH的使命是了解和开发精神障碍的治疗方法。最后，培训计划是 我们在这份提案中所描述的将为沃尔默女士提供一套神经基因组学的尖端技能。 父母资助的目标1和2是确定细胞类型特定的发育转录程序 在小鼠脑内受Foxp1或Foxp2调控的单核RNA测序(SnRNA-seq) 时间点。这些实验将利用之前生成的Foxp1和Foxp2 CKO小鼠 并使用Emx1.Cre发表(例如，Araujo等人，神经科学杂志2017；Usui等人，gene& 发展2017；Co等人，大脑皮质2020)。我们实验室最近还应用了单一- 核ATAC测序揭示基因调控和信号转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》)。将这种染色质可及性方法与 在细胞类型水平上的基因表达，应该提供一个新的分辨率水平来理解这些 转录因子组织发育信号级联。如下所述，瑞秋·沃尔默将 通过使用为SnRNA-seq提出的相同的Foxp1和Foxp2 CKO小鼠来提高亲本赠款的目标； 然而，她将在同一时间点应用SnATAC-seq来了解染色质的可及性。这间牢房- 特定的方法将允许我们缩小Foxp1和Foxp2的直接转录靶标，从而驱动 在这些模型系统中观察到的表型，如皮质迁移受损和行为不灵活。