Parameters for stable Notch-independent Her6 oscillations across a frequency spectrum in neural stem cell populations

Abstract

Neural proliferation zones drive strong and persistent growth of the developing vertebrate brain. How Notch signaling and HES/Her transcription factors in vivo maintain stable neural stem cell (NSC) populations during brain growth is not well understood. Genetic evidence revealed Her6, a Notch-independent homolog of mammalian HES1, to be essential for maintenance of zebrafish NSCs. We recombined mNeonGreen into the her6 locus and analyzed temporal Her6-mNG fluorescence profiles in vivo. Her6 is expressed dynamically in all NSCs, with a majority revealing stable oscillation, albeit from cell to cell across a wide frequency range. Her6 oscillates cell-autonomously, unaffected by inhibition of Notch, and is robustly reinitiated after experimental perturbations. Mathematical modelling predicts, and we indeed find in vivo, that Her6 oscillations prevail only when both transcript and protein degradation rate constants are equal. These intrinsic control parameters may have evolved for the Her6 oscillator to contribute to robust maintenance of NSCs.