Unbiased Identification of Novel Transcription Factors in Striatal Compartmentation and Striosome Maturation

Striatal function is dependent on neuronal compartmentation into striosomes and matrix, which are selectively affected in disease. Striatal projection neurons are GABAergic medium spiny neurons (MSNs), subtyped by selective expression of receptors, neuropeptides, and other gene families. Neurogenesis of the striosome and matrix occurs in separate waves, but the factors regulating compartmentation and neuronal differentiation following migration are largely unidentified. We performed RNA- and ATAC-seq on sorted striosome and matrix cells at postnatal day 3 using the Nr4a1-EGFP striosome reporter mouse. With a focus on the striosome, we validated the localization and/or role of Irx1, Foxf2, Olig2 and Stat1/2 in the developing striosome and the in vivo enhancer function of a striosome-specific open chromatin region 4.4 Kb downstream of the Olig2 gene. These data provide novel tools to dissect and manipulate the networks regulating MSN compartmentation and differentiation, including in human iPSC-derived striatal neurons for disease modeling and drug discovery.