The role of Notch signaling in regulating neural stem cell quiescence and termination during development

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Sood, Chhavi, Biology - Graduate School of Arts and Sciences, University of Virginia
Siegrist, Sarah, AS-Biology, University of Virginia

Multipotent cells called neural stem cells (NSCs) proliferate to produce a functional adult neural circuitry and maintain tissue homeostasis during development and in adulthood. NSCs can divide either symmetrically to increase stem cell numbers or asymmetrically to produce different types of progenies. During development, most NSCs terminate their proliferation and neurogenesis becomes restricted and in the adult tissue, NSCs are maintained in a state of quiescence in neurogenic niches. The NSC proliferation versus quiescence decisions are tightly regulated by cell-extrinsic cues: local and systemic and cell-intrinsic cues. Using Drosophila NSCs, known as neuroblasts, we aimed to understand how different signals, both intrinsic and extrinsic converge to terminate neural stem cell proliferation to promote stem cell entry into quiescence or to terminate neurogenesis during development. In the Drosophila central brain, most neuroblasts stop proliferation in a well-defined manner at the end of embryogenesis to enter quiescence and during pupal development to terminate neurogenesis. So do these transitions from proliferative to non-proliferative state share similar regulatory mechanisms even though they occur at two separate developmental time points?
In this thesis, I sought to answer this question by investigating the role of Notch signaling in neuroblast entry into quiescence and neuroblast elimination. Notch pathway is an evolutionarily conserved juxtracrine pathway that in the Drosophila central brain allows for cross-talk between neuroblasts and their newborn progeny and neuroblasts and their glial niche. Thus, Notch signaling acts as one of the cell extrinsic cues. In contrast, cell intrinsic cues are expressed in the neuroblasts and include temporally expressed transcription factors and RNA-binding proteins called temporal factors.
I show that Notch signaling is required during embryogenesis to promote neuroblast entry into quiescence and during post-embryonic development to promote neuroblast elimination and termination of neurogenesis. Interestingly, Notch signaling employs different mechanisms to promote neuroblast entry into quiescence and to promote neuroblast elimination. During neuroblast entry into quiescence, Notch signaling works in parallel with the temporal transcription factors to promote expression of Dacapo and drive cell cycle exit of neuroblasts. Moreover, in quiescent neuroblasts low to no Notch activity is required for neuroblast reactivation in response to dietary nutrients and in a PI3-kinase regulated manner. In contrast, to promote neuroblast elimination and termination of neurogenesis, Notch signaling regulates the expression of temporal factors. During post-embryonic development, Notch signaling restricts the expression of the early temporal factors, Castor, Seven-up and Imp (IgF-II mRNA binding protein) and promotes the expression of the late acting temporal factor, Syncrip and E93 to control the timing of temporal transition in the neuroblasts.
We conclude that Notch signaling is required for both neuroblast entry into quiescence and elimination and that context-dependent Notch signaling uses different effectors to regulate proliferation decisions. Thus, a common signaling pathway can regulate two developmentally distinct transitions between proliferation and non-proliferation of stem cells. Our work also highlights a different role for Notch signaling as a temporal regulator of stem cell proliferation. While Notch signaling is well known for its role in regulating binary cell fate decisions, it is becoming more apparent that Notch signaling also plays important roles in binary temporal decisions, in this case, early versus late.

PHD (Doctor of Philosophy)
Notch Signaling, Neuroblasts, Quiescence, Termination, Temporal factors, Drosophila
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