Functional investigations of Foxp1 and Foxp2 in Drd1 spiny projection neurons

Drd1 多刺投射神经元中 Foxp1 和 Foxp2 的功能研究

基本信息

批准号：
10475087
负责人：
Newaz Ibrahim Ahmed
金额：
$ 3.28万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2023-07-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10475087
关键词：
Adult Affect Age Behavior Behavioral Brain Cell Nucleus Cells Complex Corpus striatum structure DNA Sequence Alteration Data Deletion Mutation Development Disease Dopamine Receptor Embryo Etiology FOXP1 gene FOXP2 gene Functional disorder Future Gene Expression Genes Genetic Transcription Genomic approach Goals Heritability Heterodimerization Impairment Individual Investigation Knock-out Knockout Mice Knowledge Language Language Disorders Link Mediating Molecular Motor Mus Mutation Nature Neurodevelopmental Disorder Neurons Pathway interactions Patients Pattern Performance Recurrence Risk Role Small Nuclear RNA Social Behavior Social Functioning Social Interaction Speech Speech Development Testing Time Ultrasonics Variant autism spectrum disorder base behavioral genomics cell type conditional knockout de novo mutation experimental study genetic manipulation human fetal brain insight motor behavior motor impairment motor learning mouse model neurodevelopment neuropsychiatric disorder open field behavior postnatal pup repetitive behavior risk variant single-cell RNA sequencing social therapeutic target transcription factor transcriptome sequencing vocalization

项目摘要

Project Summary Individuals with mutations in either FOXP1 or FOXP2 have speech and language deficits and/or autism spectrum disorder (ASD). Mutations of Foxp1 or Foxp2 in mice manifest in ASD-relevant behaviors, such as repetitive behaviors, altered vocalizations, and impaired motor learning. Recent studies have identified neuronal cell-types most likely to be disrupted across diverse genetic mutations linked to ASD, including deep layer cortical neurons and striatal dopamine receptor 1 (Drd1) and dopamine receptor 2 (Drd2) expressing spiny projections neurons (SPNs). FOXP1 is equivalently expressed in both Drd1 and Drd2 SPNs while FOXP2 has enriched expression in Drd1 SPNs. Studies have found that a Drd2 specific knockout of Foxp1 results in reduced specification of Drd2 SPNs, increased intrinsic excitability of Drd2 SPNs, deficits in motor learning, and altered striatal projection patterns. Conversely, Foxp1 expression in Drd1 SPNs is not required for specification of Drd1 SPNs, motor learning or proper striatal projections. The enriched expression of Foxp2 in Drd1 SPNs may compensate for the loss of Foxp1. I therefore hypothesize that Foxp1 and Foxp2 have compensatory functions in Drd1 SPNs. Using Drd1-targeted conditional knockout of Foxp1, Foxp2, or both, I will test this hypothesis in two Aims. In Aim 2, I will test the requirement for either of these transcription factors in motor relevant (rotarod, open field) and socially relevant (social interaction, pup vocalizations) behaviors. In Aim 2, I will determine cell-specific gene expression changes with loss of either of these transcription factors by comparing the results of single-nuclei RNA sequencing across multiple relevant time points. Successful completion of these aims will provide a broader understanding of the role of vulnerable cell-types in brain development and the pathophysiology of ASD. Moreover, I will gain a deeper insight into the functional cell- type-specific roles of Foxp1 and Foxp2, two transcription factors that are at risk in monogenic causes of neurodevelopmental disorders, including those that impact the development of speech and language.

项目摘要在FOXP1或FOXP2中有突变的人有语音和语言缺陷和/或自闭症频谱障碍（ASD）。小鼠中FOXP1或FOXP2的突变表现在与ASD相关的行为中，例如重复行为，发声改变和运动学习受损。最近的研究已经确定神经元细胞类型最有可能破坏与ASD相关的多种基因突变，包括深层皮质神经元和纹状体多巴胺受体1（DRD1）和多巴胺受体2（DRD2）表达多刺预测神经元（SPNS）。 FOXP1在DRD1和DRD2 SPN中均等效地表达 FOXP2在DRD1 SPNS中具有丰富的表达。研究发现FOXP1的DRD2特异性淘汰导致DRD2 SPN的规格减少，DRD2 SPN的内在兴奋性增加，电动机缺陷学习和改变纹状体投影模式。相反，不需要DRD1 SPN中的FOXP1表达用于规格DRD1 SPN，运动学习或适当的纹状体预测。 FOXP2的丰富表达在DRD1中，SPN可能会弥补FOXP1的损失。因此，我假设FOXP1和FOXP2有 DRD1 SPNS中的补偿功能。使用FOXP1，FOXP2或两者兼有DRD1针对的条件淘汰将在两个目标中检验这一假设。在AIM 2中，我将测试这些转录因子中的任何一个的要求在电动机相关（Rotarod，开放场）和与社会相关的（社交互动，幼崽发声）行为中。在 AIM 2，我将确定细胞特异性基因表达的变化，并通过这些转录因子中的任何一个丢失比较跨多个相关时间点的单核RNA测序的结果。成功的这些目标的完成将为脆弱的细胞类型在大脑中的作用提供更广泛的了解 ASD的发展和病理生理学。此外，我将对功能细胞的深入了解 - FOXP1和FOXP2的类型特异性作用，两个转录因子在单基因原因中有风险神经发育障碍，包括影响语音和语言发展的神经发育障碍。