Keeping Neural Progenitors on a Short Leash: Distinguishing Intermediate Progenitors from Stem Cells in Developing Drosophila Optic Lobe and Central Brain.

Abstract

Producing intermediate progenitors is one of the critical strategies for stem cells to amplify their output and generate diversity, allowing stem cells to meet demanding requirement during development, homeostasis and tissue repair. In contrast to stem cells, intermediate progenitors possess restricted developmental potential limiting the number and types of their progeny. Failure to establish or maintain restricted potential can perturb tissue development and homeostasis, and probably contributes to tumor initiation. My thesis work revealed the mechanisms that distinguish intermediate progenitors from stem cells during the neurogenesis in both central brain and optic lobe of fruit fly Drosophila larval brain.

By examining neuroepithelial stem cell lineage in larval optic lobe, I showed that the restricted potential of intermediate progenitors is established through highly ordered sequential steps precisely paced by a spatial fluctuation of Notch activity. I identified the intermediate cell types during the differentiation of neuroepithelial stem cells into intermediate progenitors and Notch activities in those cell types indicate that while down-regulation of Notch is required for generating intermediate progenitors, up-regulation of Notch immediately before the transition is critical to prevent premature differentiation. Notch signaling plays two roles in this process: maintains the neuroepithelial stem cell identify via downstream target aop and prevents premature differentiation into intermediate progenitors by raising the threshold of response to pointP1.

Using central brain type II neuroblast lineages as the model system, I showed that the restricted potential of intermediate neural progenitors (INPs) needs to be actively maintained after correct specification and identified a novel transcription factor earmuff as the major factor maintaining restricted potential and preventing dedifferentiation of INPs. earmuff mutant shows ectopic generation of neural stem cells although the asymmetric division of neural stem cells or INPs and the specification of INPs are completely normal. earmuff mutant INPs can dedifferentiate back into a neural stem cell state, functionally indistinguishable from normal neural stem cells. Earmuff uses two independent mechanisms to restrict the potential of intermediate neural progenitors: promoting nuclear localization of Prospero to limit proliferation and antagonizing Notch signaling to prevent dedifferentiation.