Stem cells to synapses: regulation of self-renewal and differentiation in the nervous system.
Stem cells can divide symmetrically to expand the stem cell pool, or asymmetrically to self-renew and generate a daughter cell destined for differentiation. The balance between symmetric and asymmetric division is critical for the generation and repair of tissues, as unregulated stem cell division results in tumourous overgrowth. We are investigating the genetic networks that regulate stem cells in the Drosophila nervous system. By comparing the transcriptional profiles of symmetrically and asymmetrically dividing stem cells, we are identifying the molecular switches that regulate stem cell behaviour. During asymmetric division cell fate determinants, such as the transcription factor Prospero, are partitioned from the neural stem cell to its daughter. We showed that Prospero, acts as a binary switch between self-renewal and differentiation. We identified Prospero's target genes throughout the genome and showed that Prospero represses genes required for self-renewal and activates differentiation genes. In prospero mutants, differentiating daughters revert to a stem cell-like fate: they express markers of self-renewal, continue to proliferate, fail to differentiate and generate tumours. We are studying several proteins that work with Prospero to regulate the transition from stem cell to neuron. Neural stem cells transit through a period of quiescence at the end of embryogenesis. We discovered that insulin signalling is necessary for these stem cells to exit quiescence and reinitiate cell proliferation. We showed that a glial niche secretes the insulin-like peptides that reactivate neural stem cells in vivo. We are investigating the systemic and local signals that regulate stem cell growth and proliferation and the role of glia in inducing neural stem cell exit from quiescence.
Students can choose one of the following projects:
- Characterisation of a novel tumour suppressor in Drosophila
- Nutritional control of neural stem cell quiescence and reactivation
- Investigating the role of non-coding RNAs in neurogenesis
Techniques used include genetics, molecular biology, transgenesis, RNA interference, immunohistochemistry, confocal microscopy, live imaging, transcriptomics, genome-wide DNA-protein interaction assays and bioinformatics.