Article

Dronc caspase exerts a non-apoptotic function to restrain phospho-Numb-induced ectopic neuroblast formation in Drosophila

Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Development (Impact Factor: 6.27). 06/2011; 138(11):2185-96. DOI: 10.1242/dev.058347
Source: PubMed

ABSTRACT Drosophila neuroblasts have served as a model to understand how the balance of stem cell self-renewal versus differentiation is achieved. Drosophila Numb protein regulates this process through its preferential segregation into the differentiating daughter cell. How Numb restricts the proliferation and self-renewal potentials of the recipient cell remains enigmatic. Here, we show that phosphorylation at conserved sites regulates the tumor suppressor activity of Numb. Enforced expression of a phospho-mimetic form of Numb (Numb-TS4D) or genetic manipulation that boosts phospho-Numb levels, attenuates endogenous Numb activity and causes ectopic neuroblast formation (ENF). This effect on neuroblast homeostasis occurs only in the type II neuroblast lineage. We identify Dronc caspase as a novel binding partner of Numb, and demonstrate that overexpression of Dronc suppresses the effects of Numb-TS4D in a non-apoptotic and possibly non-catalytic manner. Reduction of Dronc activity facilitates ENF induced by phospho-Numb. Our findings uncover a molecular mechanism that regulates Numb activity and suggest a novel role for Dronc caspase in regulating neural stem cell homeostasis.

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    • "In addition, PP2A interacts with Baz via its catalytic subunit (Mts) and dephosphorylates Baz at the conserved serine 1085, which is important for the proper cell polarity in embryonic neuroblasts [60]. Moreover, PP2A can directly dephosphorylate Numb to facilitate the repression of neuroblast self-renewal [61]. "
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    • "The function of Numb is regulated at two levels: its asymmetric localization and its activity as an antagonist of Notch signaling [11], [13], [14]. Recently, Polo kinase-mediated phosphorylation was shown to modulate Numb activity in Drosophila NSCs [15]. Overexpression of a mutant form of Numb mimicking the hyper-phosphorylated form (Numb-TS4D) interfered with the antagonistic effect of endogenous Numb on Notch signaling and resulted in ectopic neuroblasts, similar to that seen in numb mutant. "
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    • "Second, they are the major contributors of the intrinsic neurons of the adult central complex (intrinsic neurons have projections entirely within the central complex) (Bayraktar et al., 2010; Izergina et al., 2009). Third, they are more susceptible to tumor formation (Boone and Doe, 2008; Bowman et al., 2008; Ouyang et al., 2011; Weng et al., 2010). Numerous genotypes have been identified that cause the production of ectopic larval brain neuroblasts, and several of these specifically affect type II neuroblasts. "
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