Polarization and binary cell fate decisions in the nervous system
Group leader : V. Bertrand
We are analyzing how the nervous system is polarized and how this polarity drives the generation of different types of neurons.
In both vertebrates and invertebrates, neurons are often generated by asymmetric divisions of neuronal precursors such as neural stem cells. During this process a precursor cell divides asymmetrically to generate two neurons with different identities, or one neuron and a new precursor. Precursor cells are polarized before their division, that is to say that they display two poles with different biochemical properties. During the division the two daughter cells inherite different determinants that give them distinct fates. In the nervous system the polarity of the different neuronal precursors is coordinated implying a communication between the cells.
The nematode C. elegans is a good model organism to study these mechanisms. In C. elegans the identity, connectivity and lineage history of every neuron are 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 forward genetic screens, RNAi screens or transgenesis.
Our team analyses how the nervous system is polarized and how this polarity drives the differentiation of different types of neurons using C. elegans as a model system. Our work has a potential impact on the treatment of some types of cancer as well as on the use of stem cells for cell therapy.
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.
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 recently 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 precursors is polarized. We especially analyze the polarization by a gradient of Wnt ligands and the mechanism establishing this gradient. We address this question in vivo using advanced imaging techniques.
2) How the daughter cells acquire different fates and especially how the asymmetric division machinery is connected to the terminal differentiation program of postmitotic neurons. We analyze more specifically the role of the Wnt/β-catenin pathway and the role played by chromatin factors in this process. We address this question using a combination of automated screens and high-throughput sequencing.
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.
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 1st, 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