Andrea Brand PhD FRS FMedSci, Herchel Smith Professor of Molecular Biology, Member of the Department of Physiology, Development and Neuroscience.
Stem cells to synapses: regulation of self-renewal and differentiation in the nervous system
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. 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. By comparing the transcriptional profiles of symmetrically and asymmetrically dividing stem cells, we identified Notch as a key regulator of the switch from symmetric to asymmetric division.
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 targets throughout the genome and showed that Prospero represses genes 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.
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
• Southall TD, Davidson CM, Miller C, Carr A and Brand AH (2014) Dedifferentiation of neurons precedes tumor formation in lola mutants. Developmental Cell 10.1016/j.devcel.2014.01.030
• Southall TD, Gold KS, Egger B, Davidson CM, Caygill EE, Marshall OJ and Brand AH (2013) Cell type-specific profiling of gene expression and chromatin binding without cell isolation: Assaying RNA Pol II occupancy in neural stem cells. Developmental Cell 26, 101-112
• Cheetham SW and Brand AH (2013) Insulin finds its niche. Science 340, 817-818
• Wolfram V, Southall TD, Brand AH and Baines RA (2012) The LIM-homeodomain protein Islet dictates motor neuron electrophysiological properties by regulating K+ channel expression. Neuron 75, 663-674
• Gold KS and Brand AH (2012) Transcriptome analysis of Drosophila neural stem cells. Methods in Molecular Biology 916, 99-110
• Chell JM and Brand AH (2010) Nutrition-responsive glia control exit of neural stem cells from quiescence. Cell 143(7), 1161-1173