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

• 批准号: 10254239
• 负责人: Newaz Ibrahim Ahmed
• 金额: $ 3.46万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10254239
• 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

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 Foxp1或FOXP2基因突变的个体有言语和语言缺陷和/或自闭症 谱系障碍(ASD)。Foxp1或Foxp2突变在小鼠的ASD相关行为中表现出来，例如 重复行为、发声改变和运动学习障碍。最近的研究发现 最有可能在与ASD相关的各种基因突变中被破坏的神经细胞类型，包括深 层皮质神经元与纹状体多巴胺受体1和2的表达 棘突投射神经元(SPN)。Foxp1在DRD1和DRD2 SPN中表达相同，而 Foxp2在DRD1SPN中有丰富的表达。研究发现，Foxp1的Drd2特异性敲除 结果DRD2 SPN的规格降低，DRD2 SPN的内在兴奋性增加，运动障碍 学习，并改变纹状体投射模式。相反，DRD1 SPN中的Foxp1表达不是必需的 用于指定DRD1SPN、运动学习或正确的纹状体投射。Foxp2基因的丰富表达 在DRD1中，SPN可能补偿Foxp1的损失。因此我假设Foxp1和Foxp2 DRD1SPN的代偿功能。使用针对DRD1的条件基因敲除Foxp1和/或Foxp2，即 我将在两个目标上检验这一假设。在目标2中，我将测试对这两种转录因子的需求 在运动相关(转轮，空地)和社会相关(社会互动，小狗发声)行为中。在……里面 目的2，我将通过以下方式确定这些转录因子中的任何一个丢失时细胞特异性基因表达的变化 比较多个相关时间点的单核RNA测序结果。成功 这些目标的完成将使我们更广泛地了解脆弱细胞类型在大脑中的作用 ASD的发展和病理生理学。此外，我将对功能细胞有更深入的了解- Foxp1和Foxp2这两个在单基因致病风险中的转录因子的类型特异性作用 神经发育障碍，包括那些影响言语和语言发育的疾病。