Schematized cross-section of the zebrafish adult telencephalon (left) and corresponding picture (right) showing the large distribution of neural stem cells (green, radial glial cells) along the ventricle. On the right panel, one stem cell is labeled with GFP (green), with its cell body embedded into the stem cell layer (red), overlaying telencephalic neurons (blue).
Neural stem cells are largely distributed along the ventricule
M. Krecsmarik © 2014
Neural stem cells (NSCs) are at the origin of the neurons and glia generated in the adult vertebrate brain. The success of NSC maintenance and mobilization varies widely among species, brain territories, pathological conditions and individual environment, with important physiological impacts.
Laure Bally and her team are using the zebrafish model (Danio rerio) to uncover molecular and cellular processes involved in controlling NSC pools homeostasis and fate along life.
Laure Bally-Cuif’s research addresses the molecular and cellular mechanisms controlling the specification and fate of neural progenitors (NPs) / neural stem cells (NSCs) and governing the functional organization of the vertebrate central nervous system. She opted for the zebrafish model some years ago, for its amenability to manipulate gene function and analyze cell fate in the embryo, including at the single cell level.
Recently, Laure Bally-Cuif and her lab contributed to expand the incomparable advantages of this model to adult neurogenesis and behavioral studies.
Realizations / Projects
Research conducted in her lab brought new discoveries along three main axes that they are pursuing:
1/ Embryonic neural progenitors
The embryonic neural tube is organized as an alternating pattern of neuronal clusters and neuron-free boundaries, generally corresponding to organizing centers. Laure Bally-Cuif’s work in the embryo largely aimed to decipher the molecular and cellular correlates of this organization, using as a paradigm the midbrain-hindbrain boundary (MHB). Previous work had revealed “delayed” NP populations (also called “long lasting”) at neural tube boundaries, while “actively neurogenic” NPs populated neuromeres. She and her lab demonstrated the involvement of delayed NPs in the maintenance of organizing centers, highlighting the connection between neurogenesis inhibition and the maintenance of signaling activities. While most NPs are maintained by E(spl) factors downstream of Notch signaling, they also revealed a paradoxical Notch-independent (“non-canonical”) expression for these factors in delayed NP. The remaining questions that they are currently addressing aim to further dissect the non-canonical molecular cascades encoding delayed NPs, their possible lineage relationship with neurogenic NPs, and the mechanisms driving the early dynamics of the NP state.
2/ Adult neural stem cells
The adult vertebrate brain is also organized as an alternation of constitutively neurogenic versus non-neurogenic domains where progenitors may reside but be silent. Laure Bally-Cuif’s lab and others had highlighted the high enrichment in neurogenic niches in zebrafish compared to mammals. In the dorsal telencephalon, slowly dividing radial glial cells (RGs) lining the ventricle act as NPs. They also had identified a neuroepithelial population with neural stem cell (NSC) properties at the adult MHB. This boundary maintains expression of the Notch-independent E(spl) gene her5 from embryonic stages onwards. Based on these observations, they postulated a lineage relationship between embryonic delayed NPs and adult NSCs. These studies opened a new model to address in a comprehensive manner, i.e. with access to numerous NP populations in various brain locations, key aspects of adult NSC biology: the different cell types and cellular hierarchies that can successfully drive adult neurogenesis, their lineage relationship with embryonic NP subtypes, and the events underlying the successful maintenance of germinal zones (GZ) in the adult brain. These are among the main questions that Laure Bally-Cuif and her lab are currently focusing on, using the telencephalon as main study model.
3/ Functional implications of adult neurogenesis
The generation of new neurons in the adult brain is key to the structural plasticity of neuronal circuits. In rodents, neurons born from the sub-ependymal zone of the lateral ventricle and the subgranular zone of the hippocampus (SEZ/SGZ) were implicated in long-term spatial memory and in the perception and memory of odors. Correlating evidence also suggested a role for adult neurogenesis in modulating emotional/motivational behavior, but the neuronal subtypes and maturation stages involved remained to be identified. In addition, reciprocal changes had been observed between the use of addiction drugs and neurogenesis efficiency, but the NP subtypes and mechanisms targeted by these drugs in GZs remained unknown. The widespread neurogenesis of the zebrafish adult brain, the robustness of motivational/emotional behaviors across evolution, and our success at building assays quantitatively measuring those behaviors in zebrafish, suggested that it as a good model to address these questions. Laure Bally-Cuif and her lab are taking some approaches along these lines.
• 1987 Admission to the Ecole Normale Supérieure, Paris, France
• 1994 PhD in Biology-Biochemistry, Salpêtrière Hospital and University Paris 6, France; Marion Wassef's lab
• 1994-1996 EMBO Postdoctoral fellow, Princeton University, USA; Robert K Ho's lab
• 1997-2000 Postdoctoral fellow, Helmholtz Zentrum, Germany; Wolfgang Wurst's lab
• 2000 Appointed Junior group leader, Helmholtz Zentrum Muenchen, Germany
• 2006 Appointed Research Department Head, Helmholtz Muenchen, Germany
• 2009 Appointed CNRS Research Director, Gif-sur-Yvette, France
• 2016 Appointed DR (Research Director) at the CNRS and Unit Leader at the Pasteur Institute, Paris
• Silver medal of the CNRS 2017
• Elected EMBO Member 2016
• Jansen Price of the French National Academy of Medicine 2016
• Advanced Investigator Grant, European Research Council (ERC), 2012
• Fondation pour la Recherche Médicale team, 2012
• Scientific Excellence Award, CNRS, 2010
• Chaire d’Excellence, Paris Neurosciences Graduate School, 2010
• Chaire d’Excellence Senior, French National Agency for Research (ANR), 2008
• Heinz Maier-Leibnitz award, German Research Foundation, 2006
Large-scale live imaging of adult neuro stem cells in their endogenous niche.
Oct 2015, Development