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. Symmetrically dividing stem cells exist in the optic lobe of the brain, where they convert to asymmetrically dividing neuroblasts. 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.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.

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. By identifying Prospero’s targets throughout the genome we 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 showed that insulin signalling is necessary for these stem cells to exit quiescence and reinitiate cell proliferation, we identified nutrition-responsive glial cells as the source of the insulin- like peptides that reactivate neural stem cells in vivo.

Expression of temporal transcription factors Castor (green) and Chinmo (blue) in the larval ventral nerve cord. Neurablasts in red.

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.

Selected publications:

• Chell JM and Brand AH (2010) Nutrition-responsive glia control exit of neural stem cells from quiescence Cell 143(7), 1161-1173

• Egger B, Gold KS and Brand AH (2010) Notch regulates the switch between symmetric and asymmetric neural stem cell division in the Drosophila optic lobe Development 137, 2981-2987

• Bardin AJ, Perdigoto CN, Southall TD, Brand AH and Schweisguth F (2010) Transcriptional control of stem cell maintenance in the Drosophila intestine Development 137, 705-714

• Monier B, Pelissier A, Brand AH and Sanson B (2010) An actomyosin-based barrier inhibits cell mixing at compartmental boundaries in Drosophila embryos Nature Cell Biology 12, 60-65

• Southall TD and Brand AH (2009) Multiple transcription factor binding identifies neural stem cell gene regulatory networks EMBO J. 28, 3799-807

Two neural stem cell clones in the larval brain, labelled in red. Neuroblast nuclei are green.