Single-Cell Analysis of Foxp1-Driven Mechanisms Essential for Striatal Development

• DOI: 10.1016/j.celrep.2020.02.030
• Publication Date: 2020-03-03T16:53:51Z
• Authors: Ashley G. Anderson; Ashwinikumar Kulk...; Matthew Harper; Genevieve Konopka
• Keywords: Mice, Knockout; Neurons; 0301 basic medicine; 0303 health sciences; QH301-705.5; Forkhead Transcription Factors; Globus Pallidus; Article; Corpus Striatum; Up-Regulation; Mice, Inbred C57BL; Repressor Proteins; 03 medical and health sciences; Animals, Newborn; Animals; Biology (General); Single-Cell Analysis; Biomarkers; Gene Deletion; Signal Transduction

AbstractThe striatum is a critical forebrain structure for integrating cognitive, sensory, and motor information from diverse brain regions into meaningful behavioral output. However, the transcriptional mechanisms that underlie striatal development and organization at single-cell resolution remain unknown. Here, we show that Foxp1, a transcription factor strongly linked to autism and intellectual disability, regulates organizational features of striatal circuitry in a cell-type-dependent fashion. Using single-cell RNA-sequencing, we examine the cellular diversity of the early postnatal striatum and find that cell-type-specific deletion ofFoxp1in striatal projection neurons alters the cellular composition and neurochemical architecture of the striatum. Importantly, using this approach, we identify the non-cell autonomous effects produced by disruptingFoxp1in one cell-type and the molecular compensation that occurs in other populations. Finally, we 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 withFOXP1loss-of-function mutations. These data reveal cell-type-specific transcriptional mechanisms underlying distinct features of striatal circuitry and identify Foxp1 as a key regulator of striatal development.