Developmental genetics of neural stem cells

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Abstract In the Drosophila nerve cord, neuronal precursor cells called neuroblasts (NBs) undergo a variable number of self-renewing asymmetric divisions. At some point during development, these cells either become quiescent but re-enter cell cycle later, terminally divide into neurons, or undergo apoptosis. No one knows whether these precursors measure elapsed time or count the number of divisions before exiting the cell-cycle. In the fly nervous system, NBs differ in their division potential--the number of times they undergo division. NBs must decide to enter or exit from the cell cycle, but whether their read out is the time elapsed or a cell cycle count is unknown. Additionally, we do not know whether the mechanism(s) is regulated from within the cell or extrinsic to the cell. These are difficult questions to address. By examining different types of NBs, we hope to reveal genes and mechanisms that regulate the cell cycle entry and exit, and the division potential of NBs during development. During the course of our work on genetic regulation of asymmetric division of precursors, we isolated a mutation that caused additional divisions of precursor cells in many lineages in the nerve cord. We cloned the gene and found that it is a member of the T-box protein family. These proteins play important roles from development to cancer. Our studies on this gene, midline, led us to believe that it regulates precursor cell entry and exit from the cell-cycle. It appears to also play a role as part of a mechanism by partnering with Prospero. Thus, our specific aims are: 1) Determine the role of Mid in the cell cycle entry and exit by neuronal stem cells, 2) Determine the regulation of mid-expression, whether it is linked to the system that it regulates or originates outside of the cells it regulates, and 3) Determine if Mid partners with Prospero to specify the division potential of precursor cells. The cell cycle entry and exit by precursors and the regulation of their division potential are exceedingly difficult problems to study. Whether these regulatory mechanisms reside within the cell or extrinsic to cells, do cells measure the time elapsed, or is there a counting mechanism that determines/interacts with the cell cycle machinery, are all unknowns. Our aims are focused on exploring these issues using a powerful genetic system. By no means is this proposal only Mid or Pros-centric, these players are entry points to tackle the above problems in biology.