Understanding the molecular mechanisms by which newly identified fly genes regulate self-renewal vs. differentiation in fly neuroblasts.
Stem cells are precursor cells capable of generating virtually any mature cell types (differentiation) found within the tissue where these stem cells reside over a prolonged period of time or in response to injury. Therefore, stem cells need to maintain their stemness (self-renewal) extensively to prevent the stem cell population from becoming depleted; consequently, a balance between self-renewal and differentiation by stem cells is of paramount importance. We use fruit fly neural stem cells (neuroblasts) as a model to study how self-renewal vs. differentiation because fly neuroblasts always divide unequally to self-renew a neuroblast and to generate an immature daughter cell called ganglion mother cell (GMC), which divides once to generate two mature neurons or glia. Asymmetric cell division allowed fly larval brains to maintain a steady population of 100 neuroblasts per brain lobe while generating thousands of neurons. Mutants that are defective in self-renewal are predicted to exhibit premature loss of neuroblasts (<100) whereas mutants that self-renew excessively are predicted to show an expansion in neuroblasts (>100). Consistent with this hypothesis, I recently demonstrated that atypical Protein Kinase C (aPKC) is a potent inducer of neuroblast self-renewal. We currently combine genetic, biochemical, and genomic approaches to identify the downstream targets of aPKC that promote neuroblast self-renewal. In addition, I previously demonstrated that the transcription factor Prospero (Pros) was asymmetrically partitioned into GMCs, where Pros functions to trigger differentiation for generation of mature cells. We presently employ combination of genomic and bioinformatic approaches to identify the targets of Pros required for activation of GMC differentiation. In parallel, we continue functional analysis of the additional self-renewal defective or differentiation defective mutants that I identified during my post-doctoral study in order to identify genes responsible for the mutant phenotype. Finally, we will apply the insight gained from studying genes that regulate fly neuroblast self-renewal to a clinically relevant vertebrate system such as mouse to test the roles of these fly genes in regulation of vertebrate neural stem cell self-renewal. My long-term goal is identify many signaling pathways expressed in both insect and vertebrate neural stem cells, and contribute to our understanding of neural stem cells in birth defects, regenerative medicine and cancer biology.