The Orphan Nuclear Receptor TLX Represses Hes1 Expression, Thereby Affecting NOTCH Signaling and Lineage Progression in the Adult SEZ

Abstract

Summary: In the adult subependymal zone (SEZ), neural stem cells (NSCs) apically contacting the lateral ventricle on activation generate progenitors proliferating at the niche basal side. We here show that Tailless (TLX) coordinates NSC activation and basal progenitor proliferation by repressing the NOTCH effector Hes1. Consistent with this, besides quiescence Hes1 expression also increases on Tlx mutation. Since HES1 levels are higher at the apical SEZ, NOTCH activation is increased in Tlx−/− NSCs, but not in surrounding basal progenitors. Underscoring the causative relationship between higher HES1/NOTCH and increased quiescence, downregulation of Hes1 only in mutant NSCs normalizes NOTCH activation and resumes proliferation and neurogenesis not only in NSCs, but especially in basal progenitors. Since pharmacological blockade of NOTCH signaling also promotes proliferation of basal progenitors, we conclude that TLX, by repressing Hes1 expression, counteracts quiescence and NOTCH activation in NSCs, thereby relieving NOTCH-mediated lateral inhibition of proliferation in basal progenitors. : Ciccolini and colleagues show that Tailless (TLX) affects quiescence and lineage progression by cell-autonomous and non-cell-autonomous mechanisms. In apical neural stem cells (NSCs), TLX downregulates Hes1, thereby decreasing NOTCH signaling. This promotes transcription of the proneural gene Mash1 and NSC activation. Moreover, it also decreases NOTCH-mediated lateral inhibition of basal progenitor proliferation. Keywords: neural stem cells, Tlx, NOTCH signaling, neurogenesis, Hes1, quiescence, subependymal zone, Mash1