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 cell behaviour. Neural stem cells in the adult brain exist primarily in a quiescent state but can be reactivated in response to changing physiological conditions. How do stem cells sense and respond to metabolic changes? In the Drosophila central nervous system, quiescent neural stem cells are reactivated synchronously in response to a nutritional stimulus. We showed that feeding triggers insulin production by blood-brain barrier glial cells, activating the insulin/IGF pathway in underlying neural stem cells and stimulating their growth and proliferation. More recently, we discovered that gap junctions in the blood-brain barrier glia mediate the influence of metabolic changes on stem cell behaviour, enabling glia to respond to nutritional signals and reactivate quiescent stem cells.
The ability to reprogram differentiated cells into a pluripotent state has revealed that the differentiated state is plastic and reversible. Mechanisms must be in place to prevent neurons from dedifferentiating to a multipotent, stem cell-like state. We discovered that the BTB-Zn finger transcription factor, Lola, is required to maintain neurons in a differentiated state. In lola mutants, neurons dedifferentiate, turn on neural stem cell genes and begin to divide, forming tumours. Thus, neurons rather than stem cells or intermediate progenitors are the tumour-initiating cells in lola mutants.
Cell-type specific transcriptional profiling is key to understanding cell fate specification and function. We developed ‘Targeted DamID’ (TaDa) to enable cell-specific profiling without cell isolation. TaDa permits genome-wide profiling of DNA- or chromatin-binding proteins without cell sorting, fixation or affinity purification.
• 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