Zfhx3 is required for the differentiation of late born D1-type medium spiny neurons

The striatum, the major component of the basal ganglia, consists of the caudate-putamen, nucleus accumbens and olfactory tubercle. The striatal principal projection neurons are comprised of medium spiny neurons (MSNs) with two dopamine receptors: DRD1 (D1 MSNs) and DRD2 (D2 MSNs). In the present study, we demonstrate that Zfhx3 is strongly expressed in the boundary of the subventricular zone (SVZ)/mantle zone (MZ) of the lateral ganglionic eminence (LGE), and its expression in the striatum is downregulated during the first postnatal week. At the cellular level, Zfhx3 is selectively expressed in immature D1 MSNs. In Zfhx3 conditional knockouts, we observed an accumulation of progenitors in the LGE SVZ at E16.5 and P0, and an increase in apoptosis in the postnatal striatum. BrdU birthdating experiments revealed that late born D1 MSN production was compromised. Accordingly, we observed a significant reduction in the number of D1 MSNs, whereas the number of D2 MSNs remained unaffected in the striatum of Zfhx3 conditional knockouts at P11. We concluded that Zfhx3 plays a critical role in the differentiation and survival of late born D1 MSNs.