Andrea Brand PhD FRS FMedSci
Andrea is Herchel Smith Professor of Molecular Biology and a member of the Department of Physiology, Development and Neuroscience.
Stem cells to synapses: regulation of self-renewal and differentiation in the nervous system
Co-workers: Janina Ander • Elizabeth Caygill • Seth Cheetham • Esteban Contreras-Sepulveda • Melanie Cranston • Abhijit Das • Catherine Davidson • David Doupé • Paul Fox • Katrina Gold • Jun Liu • Owen Marshall • Leo Otsuki • Chloe Shard • Tony Southall • Pauline Spéder • Christine Turner
Plain English: One of the goals of research in neurobiology is to repair or regenerate neurons after damage to the brain or spinal cord. Before we can understand how to repair the nervous system, however, we must first learn how the nervous system is put together. Of all the tissues and organs in the human body the nervous system is the most intricate and complex, consisting of more than 1012 neurons. These neurons make precise connections with each other to form functional networks that can transmit information at amazing speed over considerable distances.
Neurons are produced by multipotent precursors called stem cells. Neural stem cells divide in a self-renewing manner, generating daughter cells that give rise to different types of neurons. The aim of our work is to identify the genes that direct the different behaviours of cells in the developing nervous system. When we identify the genes that specify the characteristic behaviours of each of the different cell types in the nervous system, it may become possible to manipulate them in such a way as to induce stem cells to become neurons at will, or induce neurons to regenerate.
Research interests:
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
Selected publications:
• Chell JM and Brand AH (2010) Nutrition-responsive glia control exit of neural stem cells from quiescence. Cell 143(7), 1161-1173
• 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 Biology916, 99-110
• Caygill EE. Gold KS and Brand AH (2012) Molecular profiling of neural stem cells in Drosophila melanogaster. in The making and un-making of neuronal Circuits in Drosophila Ed. Bassem AH
• Murray MJ, Southall TD, Liu W, Fraval H, Lorensuhewa N, Brand AH and Saint R (2013) Snail dependent repression of the RhoGEF Pebble is required for gastrulation consistency in Drosophila melanogaster. Development, Genes and Evolution, 222 (6), 361-368
Expression of temporal transcription factors Castor (green) and Chinmo (blue) in the larval ventral nerve cord. Neurablasts in red.
Two neural stem cell clones in the larval brain, labelled in red. Neuroblast nuclei are green.
Drosophila neural stem cells (blue) divide asymmetrically during embryogenesis to self-renew and generate differentiating daughter cells (red). Neural stem cells then enter a period of quiescence (grey) from which they are reactivated to expand the stem cell pool (purple) and generate the neurons of the adult nervous system (green).
Lineage tracing in the Drosophila optic lobes of the Drosophila brain, using the Gtrace system. Cells currently expressing the transcription factor Optix expresses RFP (red); cells descended from Optix-expressing cells express GFP (green). The transcription factor Dachsund (blue) marks the lamina region of the developing visual system.