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

Abstract

SUMMARYDrosophila 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.

dp53 Restrains Ectopic Neural Stem Cell Formation in the Drosophila Brain in a Non-Apoptotic Mechanism Involving Archipelago and Cyclin E

“…We demonstrate that overexpression of dp53 abolishes ectopic neuroblast formation in either numb mutant or animals overexpressing Numb-TS4D, a recently genetically engineered dominant-negative form of Numb [15]. At the mechanistic level, we show that the rescuing effect of dp53 is largely mediated by Cyc E, rather than Dap/p21, and that dp53 likely acts through the recently identified p53 target Ago to influence Cyc E. Our results underscore an intimate relationship between cell cycle progression and stem cell homeostasis and suggest that manipulating levels of cell cycle regulators such as Cyc E and Ago that can delay the cell cycle without stopping it might be therapeutically beneficial for the targeting of CSCs.…”

Polo Kinase Phosphorylates Miro to Control ER-Mitochondria Contact Sites and Mitochondrial Ca 2+ Homeostasis in Neural Stem Cell Development

“…Importantly, the NB and IP loss caused by Polo-OE was also partially rescued by pharmacological interventions that reduce Ca 2+ mito (Figure S5K, L). This effect was specific, as NB and IP losses caused by Numb-OE (Ouyang et al, 2011) was not rescued by similar treatments (Figure S5M). The Polo-Miro axis thus plays a physiological role in regulating NB maintenance via Ca 2+ mito homeostasis.…”

The Role of Apoptosis-Induced Proliferation for Regeneration and Cancer

“…These experiments show that caspases can be active to perform certain functions without inducing apoptosis. Low levels of caspase activity in fact plays various nonapoptotic roles, including sensory neuron development (Geisbrecht and Montell 2004; Kanuka et al 2005; Kuranaga et al 2006; Oshima et al 2006; Ouyang et al 2011), cell migration (Geisbrecht and Montell 2004), cytoskeletal rearrangements (Kuranaga et al 2006), spermatid differentiation (De Maria et al 1999; Arama et al 2003; Huh et al 2004; Arama et al 2007; Bader et al 2011), and cell fate decision (De Maria et al 1999; and reviewed by Miura 2012). Together, these observations indicate that caspase activity can be maintained below the threshold of apoptosis execution, and conceptually, this may allow cells to signal for proliferation prior to the onset of the rapid cell death program.…”