Stem cells have the remarkable ability to give rise to both self-renewing and differentiating daughter cells. Drosophila neural stem cells segregate cell fate determinants from the self-renewing stem cell to the differentiating daughter at each division. We have shown that one such determinant, the homeodomain transcription factor Prospero, regulates the choice between self-renewal and differentiation. We identified the in vivo binding sites of Prospero throughout the genome and demonstrated, by expression profiling on DNA microarrays, that Prospero represses genes required for self-renewal and, surprisingly, is also required to activate genes for terminal differentiation. We have shown that Prospero acts as a binary switch between self-renewal and differentiation. In the absence of Prospero differentiating daughters revert to a stem cell-like fate: they express markers of self-renewal, proliferate, fail to differentiate and form small tumours. By identifying neural stem cell-specific genes, and genes specific for differentiating daughters, we can begin to assess the potential for redirecting post-mitotic cells to divide in a regenerative manner, or to induce stem cells to differentiate.

In vertebrates, adult neural stem cells can proliferate in response to injury. We have discovered that Drosophila ventral midline cells, which normally divide only once, can undergo an extra cell division if a sibling midline cell is destroyed. Remarkably, the regenerated midline cell differentiates appropriately to replace the damaged cell. We aim to uncover the molecules that enable, or inhibit, neural regeneration. These molecules will be key targets for mutagenesis and targeted misexpression, as well as potential drug targets.