Notch-independent Her6 contributes to control of neural stem cell maintenance by shifting Notch signaling from lateral inhibition towards lateral induction mode

Abstract

The growing brain faces the challenge to establish stable spatially defined neural proliferation zones that accomplish both neural stem cell (NSC) maintenance and dynamic neurogenesis. We investigated the relative impact of Notch signaling, Notch-dependent, and Notch-independent HES/Her transcription factors on target gene expression in the larval zebrafish brain. Both genetic evidence and transcriptional network analysis reveal a pivotal role of Her6, a Notch-independent HES1 homolog, in NSC control. Her6 at G1, and Notch signaling at G2, regulate distinct cell cycle control genes, favoring arrest. Her6 and Notch activity combined differentially control delta, jagged, lfng and notch3 expression to potentially shift Notch signaling mechanisms from Delta-driven lateral inhibition to Jagged-Notch3-mediated lateral induction. Indeed, we detect in situ spatial expression profiles consistent with lateral induction in high her6 expressing regions of the larval and adult brain. Her6-dependent lateral induction may spatially organize coherent populations of long-term NSCs in active proliferation zones.