Dorsal-Ventral Differences in Neural Stem Cell Quiescence Are Induced by p57(KIP2)/Dacapo

Quiescent neural stem cells (NSCs) in the adult brain are regenerative cells that could be activated therapeutically to repair damage. It is becoming apparent that quiescent NSCs exhibit heterogeneity in their propensity for activation and in the progeny that they generate. We discovered recently that NSCs undergo quiescence in either G(0) or G(2) in the Drosophila brain, challenging the notion that all quiescent stem cells are G(0) arrested. We found that G(2)-quiescent NSCs become activated prior to G(0) NSCs. Here, we show that the cyclin-dependent kinase inhibitor Dacapo (Dap; ortholog of p57(KIP2)) determines whether NSCs enter G(0) or G(2) quiescence during embryogenesis. We demonstrate that the dorsal patterning factor, Muscle segment homeobox (Msh; ortholog of MSX1/2/3) binds directly to the Dap locus and induces Dap expression in dorsal NSCs, resulting in G(0) arrest, while more ventral NSCs undergo G(2) quiescence. Our results reveal region-specific regulation of stem cell quiescence.