Abstract
Neural stem cells (NSCs) are able to self-renew while giving rise to neurons and glia that comprise a functional nervous system. However, how NSC self-renewal is maintained is not well understood. Using the Drosophila larval NSCs called neuroblasts (NBs) as a model, we demonstrate that the Hairy and Enhancer-of-Split (Hes) family protein Deadpan (Dpn) plays important roles in NB self-renewal and specification. The loss of Dpn leads to the premature loss of NBs and truncated NB lineages, a process likely mediated by the homeobox protein Prospero (Pros). Conversely, ectopic/over-expression of Dpn promotes ectopic self-renewing divisions and maintains NB self-renewal into adulthood. In type II NBs, which generate transit amplifying intermediate neural progenitors (INPs) like mammalian NSCs, the loss of Dpn results in ectopic expression of type I NB markers Asense (Ase) and Pros before these type II NBs are lost at early larval stages. Our results also show that knockdown of Notch leads to ectopic Ase expression in type II NBs and the premature loss of type II NBs. Significantly, dpn expression is unchanged in these transformed NBs. Furthermore, the loss of Dpn does not inhibit the over-proliferation of type II NBs and immature INPs caused by over-expression of activated Notch. Our data suggest that Dpn plays important roles in maintaining NB self-renewal and specification of type II NBs in larval brains and that Dpn and Notch function independently in regulating type II NB proliferation and specification.
Highlights
Neural stem cells (NSCs), like other stem cells, maintain their undifferentiated proliferative status while undergoing many rounds of cell division to produce a diverse array of neurons and glia
To understand how the self-renewal of NBs is regulated, we investigated the function of the Drosophila bHLH transcriptional repressor Deadpan (Dpn), a member of the Hairy and Enhancerof-Split (Hes) family that is expressed in all neural precursors [15]
To examine whether Dpn is required for maintaining NB self-renewal, we first compared the number of type I and type II NBs in wild type and dpn mutant brains at the late 3rd instar larval stage (4 days after larval hatching [ALH]) using Miranda (Mira), which marks all larval NBs, and Asense (Ase), which is expressed in type I but not type II NBs
Summary
Neural stem cells (NSCs), like other stem cells, maintain their undifferentiated proliferative status while undergoing many rounds of cell division to produce a diverse array of neurons and glia. Proliferating NSCs are maintained through symmetric divisions, which expand the NSC pool, as well as self-renewing asymmetric cell divisions, which produce one daughter that becomes a NSC and another daughter with limited proliferative potential that will produce differentiated progeny. Maintaining the self-renewal of NSCs is critical for the proper formation and homeostasis of the nervous system. Deciphering the mechanisms underlying the balance between NSC self-renewal and neuronal differentiation is important for understanding normal neurogenesis as well as the pathology of diseases that result from perturbations in NSC selfrenewal. The mechanisms maintaining NSC self-renewal and how NSC proliferation and differentiation are balanced are just beginning to be understood
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