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

The growing brain faces the challenge to establish neural stem cell (NSC) populations that accomplish both stable NSC maintenance and dynamic generation of progenitors. Lineage-specific scRNA-seq and time series transcriptome analyses upon overexpression of Notch signaling components in the larval zebrafish brain reveal differential contributions of Notch signaling and Notch-independent Her6, a HES1 homolog, to NSC regulation. Notch signaling and Her6 distinctly regulate cell cycle genes to control G0/G1 or G2 exit and promote quiescence. Her6 and Notch activity combined differentially control delta, jagged, lfng and notch3 expression to potentially shift Notch signaling from Delta-driven lateral inhibition to Jagged-Notch3-mediated lateral induction. We propose that Her6 integrates cell-autonomous lineage-based information and lateral induction-mediated non-autonomous self-organization of neural proliferation zones. Her6-dependent lateral induction maintains persistent NSC patches in ventricular compartments with ongoing neurogenesis, and establishes coherent populations of long-term NSCs in active proliferation zones.