Distinguishing progenitor cells from stem cells by dampening their responses to self-renewal transcription factors. Cheng-Yu Lee^1,2,3,4, Derek Janssens⁴, Hideyuki Komori¹. 1) Center for Stem Cell Biology, Life Sciences Institute; 2) Division of Molecular Medicine and Genetics, Department of Internal Medicine; 3) Department of Cell and Developmental Biology; 4) Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, MI 48109.

   Tissue-specific stem cells generate functional cell types by first giving rise to progenitor cells that possess restricted developmental potential. Restricted potential allows progenitor cells to undergo limited proliferation to produce differentiated progeny. Thus, precise restriction of the developmental potential allows progenitor cells to amplify stem cell output while protecting stem cell genome However, the precise mechanisms restricting the potential in progenitor cells remain unknown. Type II neuroblasts in fly larval brain divide asymmetrically to self-renew while producing an immature intermediate neural progenitor (INP). We find that the asymmetrically inherited protein Brain tumor (Brat) and the transcription factor Earmuff (Erm) act sequentially in immature INPs to restrict their potential. This mechanism prevents INPs from reverting into neuroblasts by dampening their responses to the re-expression of neuroblast self-renewal transcription factors. Reduced erm function leads to aberrant reversion of immature INPs into neuroblasts induced by mis-expression of the self-renewal factors. Increased erm function blocks aberrant reversion of immature INPs despite mis-expressing the self-renewal factors. Our study defines a mechanism that functionally defines progenitor cells by reprograms their responses to the re-expression of the self-renewal transcription factors.