The SoxE factor Sox9 is selectively expressed in indirect pathway striatal projection neurons and regulates synaptogenesis.

Striatum, as the largest structure of the basal ganglia, serves as a center for information transmission and is critical for motor function and reward perception. However, the genetic mechanisms underlying its development require further exploration. Here, we found that Sox9, traditionally recognized as a glial marker, is uniquely expressed in striatal medium spiny neurons (MSNs), especially in Drd2-expressing indirect pathway MSNs (D2-MSNs). Intriguingly, Sox9 expression in the striatum, which is conserved in humans, is a dynamic process. It maintains a high level during the perinatal stage, and exhibits low expression levels or vanishes at the embryonic and postnatal stages, respectively. The peak period of Sox9 expression coincides with the transition from neurogenesis to synaptogenesis. Importantly, gene regulatory network analysis and gain-of-function experiments confirmed Sox9 is strongly correlated with synaptogenesis. Moreover, we identified that Sox9 regulates synaptogenesis by repressing Foxp2, a well-known synapse regulator. Furthermore, we demonstrated that the biased expression pattern of Sox9 in D2-MSNs is, at least in part, regulated by another SoxE family member Sox8, which is specifically expressed in Drd1-expressing direct pathway MSNs (D1-MSNs). Taken together, our findings reveal a new marker of D2-MSNs and identify its distinctive function in striatal development.