Continual inactivation of stem cell functional identity genes stabilizes progenitor commitment

Expanding the pool of stem cells that indirectly generate differentiated cell types through intermediate progenitors drives vertebrate brain evolution. Due to lack of lineage information, mechanistic investigation of their competency to generate intermediate progenitors remain impossible. Fly larval brain neuroblasts provide excellent models for investigating the regulation of stem cell functionality during neurogenesis. Type II neuroblasts undergo indirect neurogenesis by repeatedly dividing asymmetrically to generate a neuroblast and a progeny that commits to an intermediate neural progenitor (INP) identity. We identified Tailless as a unique regulator that maintains type II neuroblast functional identity including the competency to generate INPs. Successive inactivation during INP commitment renders refractory to activation by Notch signaling, preventing INPs from re-acquiring neuroblast functionality. We propose that continual inactivation of neural stem cell functional identity genes by histone deacetylation allows intermediate progenitors to stably commit to generate diverse differentiated cell types during indirect neurogenesis.