Spen and Nito prevent dedifferentiation of progenitors by translationally repressing E(Spl)mγ

Rapid termination of Notch signaling by asymmetrically segregated Numb is essential for specification of differentiating progeny during asymmetric stem cell division. Using Drosophila type II neuroblasts as a model, here we report that specification of the differentiating progeny also requires the expression of the Notch target E(Spl)mγ in the stem cell to be kept at low levels by the SPEN family proteins, Spen and Nito. We show that loss of Spen or Nito leads to a drastic increase in E(Spl)mγ expression in the stem cell and subsequent dedifferentiation of its progeny. Genetic and biochemical studies demonstrate that Spen and Nito maintain the expression of E(Spl)mγ in the stem cell at low levels by directly binding to two identical novel motifs in the 5'UTR to repress its translation. The low expression in the stem cell prevents excessive inheritance of E(Spl)mγ proteins by the differentiating progeny and ensures its rapid removal from the progeny. Together, our work uncovers a novel post-transcriptional mechanism regulating Notch signaling that is critical for cell fate specification during asymmetric stem cell division.