Stem Cells to Synapses: Regulation of Self-Renewal and Differentiation in the Nervous System. Andrea H. Brand, Tony D. Southall, Pauline Speder, Jun Liu, Catherine M. Davidson. The Gurdon Institute, University of Cambridge, Cambridge, United Kingdom.

   Discovering how stem cells are maintained in a multipotent state and how their progeny differentiate into distinct cellular fates is a key step in the therapeutic use of stem cells to repair tissues after damage or disease. We are investigating the genetic networks that regulate neural stem cells in Drosophila. Stem cells can divide symmetrically to expand the stem cell pool or asymmetrically to self-renew and generate a daughter cell destined for differentiation. By comparing the transcriptional profiles of symmetrically and asymmetrically dividing stem cells we are identifying key regulators of the switch from symmetric to asymmetric division. The balance between symmetric and asymmetric division is critical for the generation and repair of tissues, as unregulated stem cell division can result in tumours. For example the loss of cell fate determinants, such as the homeodomain transcription factor Prospero, causes differentiating daughter cells to revert to a stem cell-like fate: they express markers of self-renewal, continue to proliferate, fail to differentiate and generate tumours. By identifying Prosperos targets throughout the genome we showed that Prospero represses genes for self-renewal and activates differentiation genes. We are characterising co-factors that act with Prospero to promote differentiation and suppress tumour formation. The systemic regulation of stem cells ensures that they meet the needs of the organism during growth and in response to injury. A key point of regulation is the decision between quiescence and proliferation. During development, neuroblasts transit through a period of quiescence separating distinct embryonic and post-embryonic phases of proliferation. We discovered that insulin signalling from a surrounding glial niche is necessary for post-embryonic neuroblasts to exit quiescence and reinitiate cell proliferation. We are investigating the systemic and local signals that regulate stem cell growth and proliferation.