At a glance Full Project Title Dynamics and Homeostasis of Germinal Zones in the Adult Vertebrate Brain (Systematics) Project Objectives The SyStematics projects uses the teleost fish zebrafish to gain insight into the molecular, cellular and population mechanisms maintaining pools of active neural stem cells in the adult brain. It also aims to understand how these processes are perturbed in some pathological or altered physiological contexts where the homeostasis of adult neural stem pools is altered.. Project Funding E 2,499,855 Project Partners • E mmanuel Beaurepaire, Ecole Polytechnique, Palaiseau • J ean Livet, Institut de la Vision, Paris •B enjamin Simons, University of Cambridge, Cavendish Laboratory, UK Contact Details Laure Bally-Cuif Paris-Saclay Institute for Neuroscience (Neuro-PSI) UMR 9197 CNRS - Université Paris-Sud Avenue de la Terrasse, Bldg 5 F-91190 Gif-sur-Yvette T: +33 1 6982 4276 E: bally-cuif@inaf.cnrs-gif.fr W: http://neuro-psi.cnrs.fr/spip.php?article145 Radial glia and neural progenitors in the adult zebrafish central nervous system. Than-Trong E, Bally-Cuif L. Glia. 2015 May 14. doi: 10.1002/glia.22856.
Laure Bally-Cuif
cells. A cell that has a high level of Notch signalling will be quiescent, while if notch signalling is decreased the stem cell will activate,” explains Dr Bally-Cuif. The second genetic pathway is still the subject of active research, but Dr Bally-Cuif says the data on Notch signalling is very robust, and researchers continue to investigate its genetic basis. “There are several Notch receptors – we have identified one that is especially important for the maintenance of quiescence, which is Notch3,” continues Dr Bally-Cuif. “We are looking at this at two levels. The first is the single-cell level – so we are trying to understand how high Notch signalling controls quiescence. Notch is a receptor – it’s located at the cell membrane. When Notch signalling is activated it is cleaved from the membrane, moves inside the cell nucleus, and controls expression of target genes, which, in the context of stem cell quiescence, remain to be fully identified.” The project is also looking at stem cells at the population level, which Dr BallyCuif says is a highly original aspect of their research. This involves – in collaboration with a lab at Ecole Polytechnique (E. Beaurepaire) – developing novel optical tools to image the behaviour of neural stem cell populations in situ. Stem cells are considered here not as single cells, but as cells in a population, and researchers are looking at whether the behaviour of one particular cell can influence that of its neighbour. “We believe that all cells have the capacity to be quiescent or to activate, and that the state of the neighbouring cells will influence that,” explains Dr Bally-Cuif. In a germinal zone or sheet containing 1,000 stem cells, of which 50 are activated and 950 quiescent, Dr BallyCuif says the 50 activated stem cells will
be widely distributed. “You never find 2 that are next to each other. But then if you looked at the germinal zone two days later, you would also find 50 neural stem cells that are activated, but they wouldn’t be the same,” she says. “So we believe there is some regulation that occurs at the level of the population - ie. some emergent properties that will control where those activation events will be positioned within the stem cell sheet.” Some scientists are exploring the possibility of stimulating stem cells to produce neurons, as a means of replacing those lost following stroke or neurodegenerative disease. However, Dr Bally-Cuif believes this remains a distant prospect, and that more needs to be learned about the fundamental mechanisms of stem cell maintenance, recruitment and fate before endogenous stem cells can be safely manipulated. “Our project aims to understand what controls quiescence maintenance versus activation,” she says. This is very much a long-term aim, but the project’s research will also have more of an immediate impact in enabling the testing of molecules that stimulate stem cells. “If a company has small molecules that they see are capable of activating stem cells in vitro, the zebrafish could be a very good model to test them and see whether they work in vivo. They could identify whether the zebrafish develops tumours, and if the neurons that are produced properly integrate into the brain, and zebrafish neural stem cells are very similar to mammalian ones” outlines Dr Bally-Cuif. “Our work will lead to the establishment of a platform where that kind of molecule can be tested, at least as a first approximation of their efficacy and potential danger in vivo.”
Laure Bally-Cuif obtained her PhD in developmental biology and neuroscience at University Paris 6 in 1995. Following postdoctoral training at Princeton University (USA) she was recruited as a principal investigator at the Helmholtz Research Centre in Munich in 2000. She moved her research lab to the CNRS in Gif-sur-Yvette in 2010 on a CNRS Research Director position.
Nicolas Dray, CNRS staff scientist, analyzing an adult brain section at the confocal microscope.
18
EU Research