| Summary: | Summary: The striatum is a critical forebrain structure integrating cognitive, sensory, and motor information from diverse brain regions into meaningful behavioral output. However, the transcriptional mechanisms underlying striatal development at single-cell resolution remain unknown. Using single-cell RNA sequencing (RNA-seq), we examine the cellular diversity of the early postnatal striatum and show that Foxp1, a transcription factor strongly linked to autism and intellectual disability, regulates the cellular composition, neurochemical architecture, and connectivity of the striatum in a cell-type-dependent fashion. We also identify Foxp1-regulated target genes within distinct cell types and connect these molecular changes to functional and behavioral deficits relevant to phenotypes described in patients with FOXP1 loss-of-function mutations. Using this approach, we could also examine the non-cell-autonomous effects produced by disrupting one cell type and the molecular compensation that occurs in other populations. These data reveal the cell-type-specific transcriptional mechanisms regulated by Foxp1 that underlie distinct features of striatal circuitry. : The transcription factor FOXP1 is one of the top five genes associated with autism spectrum disorder and has conserved enriched expression in striatal spiny projection neurons (SPNs). Anderson et al. show at single-cell resolution that Foxp1 is critical for proper striatal development and functions within distinct striatal cell types in mice. Keywords: single-cell RNA sequencing, striatum, neurodevelopment, FOXP1, autism
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