Lgl, Pins and aPKC regulate neuroblast self-renewal versus differentiation

Abstract

The adult mammalian brain has a remarkable regenerative capacity, a fact that sustains hopes that neuronal replacement stem-cell therapy could become a reality. How new nerve cells integrate into existing brain circuits, however, is poorly understood. A new study in mice shows that newborn neurons are sensitive to existing neuronal activity, via the neurotransmitter GABA, and that this is key to these new cells' integration in adult neuronal circuits in vivo. An important question in stem cell and cancer biology is how a cell chooses to proliferate or differentiate. Drosophila larvae provide a good model for the study of this question, as neuroblasts in the brain undergo self-renewal at each cell division to produce another neuroblast and a differentiating daughter cell. Work on a series of Drosophila mutants shows that neuroblast renewal is controlled by the genes pins, lgl, and aPKC, previously shown to regulate asymmetric cell division. Overexpression of aPKC induces neuroblast self-renewal, a line of research that might eventually lead to ways of controlling neural stem cells used therapeutically. How a cell chooses to proliferate or to differentiate is an important issue in stem cell and cancer biology. Drosophila neuroblasts undergo self-renewal with every cell division, producing another neuroblast and a differentiating daughter cell, but the mechanisms controlling the self-renewal/differentiation decision are poorly understood. Here we tested whether cell polarity genes, known to regulate embryonic neuroblast asymmetric cell division1, also regulate neuroblast self-renewal. Clonal analysis in larval brains showed that pins mutant neuroblasts rapidly fail to self-renew, whereas lethal giant larvae (lgl) mutant neuroblasts generate multiple neuroblasts. Notably, lgl pins double mutant neuroblasts all divide symmetrically to self-renew, filling the brain with neuroblasts at the expense of neurons. The lgl pins neuroblasts show ectopic cortical localization of atypical protein kinase C (aPKC), and a decrease in aPKC expression reduces neuroblast numbers, suggesting that aPKC promotes neuroblast self-renewal. In support of this hypothesis, neuroblast-specific overexpression of membrane-targeted aPKC, but not a kinase-dead version, induces ectopic neuroblast self-renewal. We conclude that cortical aPKC kinase activity is a potent inducer of neuroblast self-renewal.