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: 6.46).
06/2011; 138(11):2185-96. DOI: 10.1242/dev.058347
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.
Available from: PubMed Central
- "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 . Moreover, PP2A can directly dephosphorylate Numb to facilitate the repression of neuroblast self-renewal . "
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ABSTRACT: Drosophila larval brain stem cells (neuroblasts) have emerged as an important model for the study of stem cell asymmetric division and the mechanisms underlying the transformation of neural stem cells into tumor-forming cancer stem cells. Each Drosophila neuroblast divides asymmetrically to produce a larger daughter cell that retains neuroblast identity, and a smaller daughter cell that is committed to undergo differentiation. Neuroblast self-renewal and differentiation are tightly controlled by a set of intrinsic factors that regulate asymmetric cell division (ACD). Any disruption of these two processes may deleteriously affect the delicate balance between neuroblast self-renewal and progenitor cell fate specification and differentiation, causing neuroblast overgrowth and ultimately lead to tumor formation in the fly. In this review, we discuss the mechanisms underlying Drosophila neural stem cell self-renewal and differentiation. Furthermore, we highlight emerging evidence in support of the notion that defects in asymmetric cell division in mammalian systems may play significant roles in the series of pathogenic events leading to the development of brain cancers.
Bioscience Reports 06/2014; 34(4). DOI:10.1042/BSR20140008 · 2.64 Impact Factor
Available from: Yingshi Ouyang
- "The function of Numb is regulated at two levels: its asymmetric localization and its activity as an antagonist of Notch signaling , , . Recently, Polo kinase-mediated phosphorylation was shown to modulate Numb activity in Drosophila NSCs . 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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ABSTRACT: Accumulating evidence suggests that tumor-initiating stem cells or cancer stem cells (CSCs) possibly originating from normal stem cells may be the root cause of certain malignancies. How stem cell homeostasis is impaired in tumor tissues is not well understood, although certain tumor suppressors have been implicated. In this study, we use the Drosophila neural stem cells (NSCs) called neuroblasts as a model to study this process. Loss-of-function of Numb, a key cell fate determinant with well-conserved mammalian counterparts, leads to the formation of ectopic neuroblasts and a tumor phenotype in the larval brain. Overexpression of the Drosophila tumor suppressor p53 (dp53) was able to suppress ectopic neuroblast formation caused by numb loss-of-function. This occurred in a non-apoptotic manner and was independent of Dacapo, the fly counterpart of the well-characterized mammalian p53 target p21 involved in cellular senescence. The observation that dp53 affected Edu incorporation into neuroblasts led us to test the hypothesis that dp53 acts through regulation of factors involved in cell cycle progression. Our results show that the inhibitory effect of dp53 on ectopic neuroblast formation was mediated largely through its regulation of Cyclin E (Cyc E). Overexpression of Cyc E was able to abrogate dp53's ability to rescue numb loss-of-function phenotypes. Increasing Cyc E levels by attenuating Archipelago (Ago), a recently identified transcriptional target of dp53 and a negative regulator of Cyc E, had similar effects. Conversely, reducing Cyc E activity by overexpressing Ago blocked ectopic neuroblast formation in numb mutant. Our results reveal an intimate connection between cell cycle progression and NSC self-renewal vs. differentiation control, and indicate that p53-mediated regulation of ectopic NSC self-renewal through the Ago/Cyc E axis becomes particularly important when NSC homeostasis is perturbed as in numb loss-of-function condition. This has important clinical implications.
PLoS ONE 11/2011; 6(11):e28098. DOI:10.1371/journal.pone.0028098 · 3.23 Impact Factor
Available from: Travis D. Carney
- "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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ABSTRACT: The Drosophila larval central brain contains about 10,000 differentiated neurons and 200 scattered neural progenitors (neuroblasts), which can be further subdivided into ~95 type I neuroblasts and eight type II neuroblasts per brain lobe. Only type II neuroblasts generate self-renewing intermediate neural progenitors (INPs), and consequently each contributes more neurons to the brain, including much of the central complex. We characterized six different mutant genotypes that lead to expansion of neuroblast numbers; some preferentially expand type II or type I neuroblasts. Transcriptional profiling of larval brains from these mutant genotypes versus wild-type allowed us to identify small clusters of transcripts enriched in type II or type I neuroblasts, and we validated these clusters by gene expression analysis. Unexpectedly, only a few genes were found to be differentially expressed between type I/II neuroblasts, suggesting that these genes play a large role in establishing the different cell types. We also identified a large group of genes predicted to be expressed in all neuroblasts but not in neurons. We performed a neuroblast-specific, RNAi-based functional screen and identified 84 genes that are required to maintain proper neuroblast numbers; all have conserved mammalian orthologs. These genes are excellent candidates for regulating neural progenitor self-renewal in Drosophila and mammals.
Developmental Biology 10/2011; 361(1):137-46. DOI:10.1016/j.ydbio.2011.10.020 · 3.55 Impact Factor
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