Polarization and binary cell fate decisions in the nervous system
Group leader : V. Bertrand
We are analyzing how the divisions of neuronal progenitors are regulated and how differentiated neurons are produced in a robust manner.
Neurons are often generated by asymmetric divisions of neuronal progenitors such as neural stem cells. During this process, a progenitor cell divides asymmetrically to generate two neurons with different identities, or one neuron and a new progenitor. In the nervous system, the asymmetric divisions of the different progenitors are tightly coordinated, implying a communication between cells. In addition, during nervous system development, a very precise set of different neuronal types is produced, meaning that their specification process has to be very robust.
Our team analyzes how the asymmetric divisions of neuronal progenitors are controlled and how various differentiated neuron types are produced in a robust manner. To address these questions we are using the nematode C. elegans as a model organism. C. elegans is a good system to study this process as its nervous system is simple and well characterized. In addition, in C. elegans, the lineage history of every neuron is known, the embryos are transparent and their development can be easily followed by 4D-videomicroscopy. The C. elegans system also offers numerous tools to dissect the molecular basis of biological processes such as genome-wide screens, transgenesis or CRISPR genome engineering.
By characterizing the mechanisms controlling neuronal progenitor divisions and differentiation, our work may have an impact on the development of treatments against some types of cancer or neurodegenerative diseases.
In both vertebrates and invertebrates, postmitotic neurons are often generated by asymmetric divisions of neuronal progenitors such as neural stem cells. This general mechanism used to build the nervous system raises two important questions : how are these asymmetric divisions coordinated in space and how do the daughter cells acquire different fates in a robust manner.
We address these questions using the nematode C. elegans as a model organism. In C. elegans, most neurons are generated during neurulation by asymmetric divisions oriented along the antero-posterior axis. We have shown that these terminal asymmetric divisions are regulated by a particular Wnt/β-catenin pathway. We are now trying to understand :
1) How the field of neuronal progenitors is polarized (upstream of the asymmetric divisions). We have recently observed that Wnt ligands, expressed at a higher level in the posterior of the embryo, regulate this process. We are now analyzing how these Wnt ligands polarize the neuronal progenitors using advanced in vivo imaging techniques with single molecule resolution.
2) How the daughter cells acquire different neuronal fates in a reliable manner (downstream of the asymmetric divisions). More precisely, we analyze how the Wnt/β-catenin pathway is connected to the terminal differentiation programs and have identified a novel mode of action for TCF, the key transcription factor of the Wnt pathway. We are also characterizing the mechanisms that allow this cell fate specification process to be highly robust and, in particular, the contribution of chromatin factors. We address this question using a combination of CRISPR genome engineering, in vivo quantitative imaging and single molecule RNA FISH.
The Wnt/β-catenin pathway is involved in several types of cancer and in the regulation of asymmetric divisions of neural stem cells in vertebrates. This study may therefore help identify candidate target proteins and mechanisms for future anti-cancer drug developments or regenerative medicine treatments.
June 30th, 2020
Neuronal specification in C. elegans: combining lineage inheritance with intercellular signaling
April 6th, 2020
Wnt ligands regulate the asymmetric divisions of neuronal progenitors in C. elegans embryos
February 14th, 2018
Zic Genes in Nematodes: A Role in Nervous System Development and Wnt Signaling.
September 29th, 2017
Zic-proteins are repressors of dopaminergic forebrain fate in mice and C. elegans.
March 7th, 2016
β-catenin-driven binary cell fate decisions in animal development.
September 21st, 2015
How targets select activation or repression in response to Wnt
June 30th, 2015
Atypical transcriptional activation by TCF via a Zic transcription factor in C. elegans neuronal precursors.
Murgan S, Kari W, Rothbächer U, Iché-Torres M, Mélénec P, Hobert O, Bertrand V.
May 5th, 2015
Setting-up a simple light sheet microscope for in toto imaging of C. elegans development.
July 26th, 2011
Notch-dependent induction of left/right asymmetry in C. elegans interneurons and motoneurons.
August 1st, 2010
Lineage programming: navigating through transient regulatory states via binary decisions.
June 15th, 2010
Analysis of multiple ethyl methanesulfonate-mutagenized Caenorhabditis elegans strains by whole-genome sequencing
July 1st, 2009
Wnt asymmetry and the terminal division of neuronal progenitors.
April 1st, 2009