Within the forebrain, the striatum regulates motor functions and reward behaviour via medium-sized spiny neurons (MSNs). MSNs can be divided into D1 and D2 subtypes, which are derived from a common progenitor: the lateral ganglionic eminence (LGE). However, the underlying mechanisms for MSN specification are not well understood. Now, Zhuangzhi Zhang and colleagues combine mouse genetics, several cutting-edge genomic approaches and luciferase assays to investigate MSN specification. By comparing wild-type mice with mutants in which Meis2 is conditionally deleted (Meis2-CKO), the authors reveal that MEIS2 positively regulates MSN differentiation genes. In the absence of MEIS2, LGE progenitor proliferation increases and immature MSNs accumulate in the LGE, indicating that MEIS2 is required for cell cycle exit and maturation. Next, the researchers identify candidate genes that exhibit decreased expression in Meis2-CKO animals and putative MEIS2-binding sites within their promoters. From these candidates, they show that MEIS2 directly activates Six3 and Zfp503 expression, which encode transcription factors crucial for D2 and D1 MSN generation, respectively. Finally, the authors reveal that Dlx1/2, which are required for MSN development, directly regulate Meis2 expression. Together, these data reveal a gene regulatory network for LGE neurogenesis.
