Dronc caspase exerts a non-apoptotic function to restrain phospho-Numb-induced ectopic neuroblast formation in Drosophila
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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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 · 2.85 Impact Factor
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ABSTRACT: The Drosophila central nervous system develops from polarised asymmetric divisions of precursor cells, called neuroblasts. Decades of research on neuroblasts have resulted in a substantial understanding of the factors and molecular events responsible for fate decisions of neuroblasts and their progeny. Furthermore, the cell-cycle dependent mechanisms responsible for asymmetric cortical protein localisation, resulting in the unequal partitioning between daughters, are beginning to be exposed. Disruption to the appropriate partitioning of proteins between neuroblasts and differentiation-committed daughters can lead to supernumerary neuroblast-like cells and the formation of tumours. Many of the factors responsible for regulating asymmetric division of Drosophila neuroblasts are evolutionarily conserved and, in many cases, have been shown to play a functionally conserved role in mammalian neurogenesis. Recent genome-wide studies coupled with advancements in live-imaging technologies have opened further avenues of research into neuroblast biology. We review our current understanding of the molecular mechanisms regulating neuroblast divisions, a powerful system to model mammalian neurogenesis and tumourigenesis.Advances in Experimental Medicine and Biology 01/2013; 786:79-102. DOI:10.1007/978-94-007-6621-1_6 · 2.01 Impact Factor
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ABSTRACT: Increasing evidence reveals that a subset of proteins participates in both the autophagy and apoptosis pathways, and this intersection is important in normal physiological contexts and in pathological settings. In this paper, we show that the Drosophila effector caspase, Drosophila caspase 1 (Dcp-1), localizes within mitochondria and regulates mitochondrial morphology and autophagic flux. Loss of Dcp-1 led to mitochondrial elongation, increased levels of the mitochondrial adenine nucleotide translocase stress-sensitive B (SesB), increased adenosine triphosphate (ATP), and a reduction in autophagic flux. Moreover, we find that SesB suppresses autophagic flux during midoogenesis, identifying a novel negative regulator of autophagy. Reduced SesB activity or depletion of ATP by oligomycin A could rescue the autophagic defect in Dcp-1 loss-of-function flies, demonstrating that Dcp-1 promotes autophagy by negatively regulating SesB and ATP levels. Furthermore, we find that pro-Dcp-1 interacts with SesB in a nonproteolytic manner to regulate its stability. These data reveal a new mitochondrial-associated molecular link between nonapoptotic caspase function and autophagy regulation in vivo.The Journal of Cell Biology 05/2014; 205(4):477-492. DOI:10.1083/jcb.201303144 · 9.69 Impact Factor