Intermediate neural progenitor cells (INPs) are transient amplifying fate-restricted progenitor cells generated from neural stem cells (NSCs). Transient amplification of INPs dramatically boosts the number and diversity of neurons/glia produced from NSCs and thus increases the brain complexity, whereas defects in the generation or cell fate commitment of INPs could lead to developmental neurological disorders and brain tumor formation. The long-term goal of this project is to elucidate genetic regulatory network that controls the generation and cell fate commitment of INPs using the Drosophila type II neuroblast (NB, the Drosophila NSC) lineages as a model system. Similar to NSCs in developing gyrencephalic brains, type II NBs produce large lineages by generating transient amplifying INPs. The newly generated immature INPs (imINPs) undergo a maturation process to become fate-committed mature INPs. Defects in INP maturation will lead to dedifferentiation of imINPs back to the NB fate and subsequent tumorigenic overproliferation of type II NBs. Thus, Drosophila type II NB lineages provide an excellent model for studying the generation of brain complexity and brain tumor formation. Recent findings from our lab and others show that maturation of INPs requires activation of the Fez transcription factor Earmuff by the Ets family transcription factor Pointed P1 (PntP1), which is also expressed in type II NBs to specify their identities. Erm then promotes INP maturation by exerting an inhibitory feedback on PntP1 in imINPs. Meanwhile, activation of Erm by PntP1 requires inhibition of self-renewing factors such as bHLH proteins Deadpan and Notch target E(spl)mγ in imINPs. Previous studies suggested that termination of Notch signaling in imINPs requires Numb-mediated degradation of Notch and the retromer complex-mediated trafficking mechanism to prevents aberrant endosomal accumulation and activation of Notch, but it is not clear whether any other mechanisms could be involve in regulating Notch signaling and its target expression in type II NB lineages. In this proposed project, we will investigate novel post-transcriptional mechanisms that regulate Notch signaling in type II NB lineages and INP maturation. The molecules we propose to study in this project all have human homologs and have been implicated in the development of various human cancers including glioblastoma. Therefore, deciphering the functions and mechanisms of these molecules in INP development will provide important information for understanding pathogenesis of related developmental disorders and various cancers.