Cdc20/fizzy maintains neural stem cells by suppressing necrotic cell death. Cheng-Yu Lee^1,2,3,4, Chaoyuan Kuang^4,5. 1) Center for Stem Cell Biology, Life Sciences Institute; 2) Division of Molecular Medicine and Genetics, Department of Internal Medicine; 3) Department of Cell and Developmental Biology; 4) Program in Cellular and Molecular Biology,; 5) Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, MI 48109.

   Mechanisms preventing precocious differentiation are indispensable for stem cell maintenance, but nothing is known about the cell survival mechanisms required for preserving a steady stem cell pool. Here, we show that Cdc20/Fizzy (Fzy), a conserved activator of the Anaphase-Promoting Complex/Cyclosome (APC/C), functions to maintain neural stem cell (neuroblast) viability in Drosophila larval brains independently of its well-established role in promoting cell proliferation. While a novel fzy mis-sense mutation has no effects on the maintenance of stem or precursor cell identity, it leads to programmed necrosis in neuroblasts as indicated by ultrastructural changes and molecular marker expression. Consistently, removing genes critical for the activation of apoptosis or autophagy does not suppress the loss of neuroblasts in fzy mutant brains. The point mutation occurs in the WD40 domain of Fzy but is not associated with the surfaces required for recruiting canonical Fzy substrates, suggesting that a novel APC/C-Fzy substrate is responsible for loss of neuroblasts. Importantly, neuroblasts lacking the APC/C function also undergo premature necrotic cell death. Finally, inactivating c-Jun N-terminal Kinase (JNK) signaling or removing Apoptosis inducing factor (Aif) function significantly prolongs survival of the fzy mis-sense mutant neuroblasts. Thus, Fzy suppresses neuroblast necrotic cell death by antagonizing multiple downstream pathways via an APC/C-dependent mechanism during Drosophila larval brain neurogenesis.