Foxp1 drives striatal projection neuron specification and organization via cell-type specific mechanism

The molecular mechanisms that underlie striatal development and organization remain largely 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 demonstrate that Foxp1 specifies a subpopulation of indirect pathway spiny projection neurons (iSPNs) while maintaining the striosome-matrix architecture through molecular mechanisms mediated by direct pathway spiny projection neurons (dSPNs). Functionally, Foxp1 alters striatal projection patterns both cell-autonomously and non-autonomously. We connect these changes in striatal circuitry to distinct behavioral deficits relevant to phenotypes described in patients with FOXP1 loss-of-function mutations. These data reveal novel cell-type specific transcriptional mechanisms underlying distinct features of striatal circuitry and identify Foxp1 as a key regulator of striatal development Overall design: We used 10X Genomic Chromium technology for single-cell RNA-sequencing of early post-natal mouse striatum within control mouse samples and mouse samples with deletion of Foxp1 in dopamine receptor 1 (dSPNs) expressing neurons, dopamine receptor 2 (iSPNs) neurons, or both. We used an N=4 per genotype for 16 total samples. 62,778 striatal cells passed quality control filters for the final analysis.