Prospero prevents lineage-specific loss and gain by regulating cyclin E and mitosis during Drosophila neurogenesis.

In Drosophila, neuroblasts (NBs) undergo self-renewing asymmetric divisions to generate ganglion mother cells (GMCs). Each GMC undergoes a terminal asymmetric division to generate two neurons. It was previously suggested that the loss of function of the chromatin-binding protein Prospero causes dedifferentiation of NB progeny into stem cells. Here, we revisit the role of Prospero during neurogenesis. We find that prospero loss-of-function causes CNS cells to mis- and co-express NB, GMC, and neuronal genes. A significant number of these prospero mutant neurons project axons. Therefore, NB progeny in prospero mutant do not dedifferentiate or function as stem cells. Instead, they fail to divide or undergo an extra cell division in a lineage-dependent manner. These phenotypes correlate with a misregulation of cyclin E. We also find that cells in prospero mutants are often arrested in prophase-metaphase. Mechanistically, these defects appear related to Prospero's extensive chromatin-binding activity and mediating large-scale gene expression regulation. Finally, additional progressive cell death in prospero mutants is not observed. These results expand our knowledge of the complex role of Prospero during neurogenesis.