Dissecting Hes-centered transcriptional networks in neural stem cell maintenance and tumorigenesis inDrosophila

Abstract

Neural stem cells divide during embryogenesis and post embryonic development to generate the entire complement of neurons and glia in the nervous system of vertebrates and invertebrates. Studies of the mechanisms controlling the fine balance between neural stem cells and more differentiated progenitors have shown that in every asymmetric cell division progenitors send a Delta-Notch signal back to their sibling stem cells. Here we show that excessive activation of Notch or overexpression of its direct targets of the Hes family causes stem-cell hyperplasias in the Drosophila larval central nervous system, which can progress to malignant tumours after allografting to adult hosts. We combined transcriptomic data from these hyperplasias with chromatin occupancy data for Dpn, a Hes transcription factor, to identify genes regulated by Hes factors in this process. We show that the Notch/Hes axis represses a cohort of transcription factor genes. These are excluded from the stem cells and promote early differentiation steps, most likely by preventing the reversion of immature progenitors to a stem-cell fate. Our results suggest that Notch signalling sets up a network of mutually repressing stemness and anti-stemness transcription factors, which include Hes proteins and Zfh1, respectively. This mutual repression ensures robust transition to neuronal and glial differentiation and its perturbation can lead to malignant transformation.

A Notch-dependent transcriptional mechanism controls expression of temporal patterning factors in Drosophila medulla

“…In type II NBs, Dpn depends on Notch signaling, and loss of Dpn causes premature differentiation 37,88 . However, in type I NBs, Dpn is not lost when Notch signaling is lost, and Notch signaling seems dispensable for the self-renewing abilities of NBs 39–41 . In the medulla neuroblasts, we also observed that in Su(H) mutant clones, the clone size and neuroblast proliferation are not significantly affected.…”

“…Ectopic activation of Notch signaling in the progeny causes them to revert back into neuroblasts and over-proliferate, while inhibition of Notch signaling in type II NBs eliminated the whole lineage [36][37][38][39] . In contrast, in most type I NB lineages, loss of N signaling does not affect neuroblast maintenance, and it was shown that E(spl) complex proteins and Deadpan act redundantly to maintain the un-differentiated state (stemness) of neuroblasts by repressing differentiation genes [39][40][41] . Notch signaling is also involved in controlling the daughter cell proliferation modes specifically the type I to type 0 switch in embryonic VNC NBs 42,43 .…”