Morphogenesis of the vertebrate brain

Our group is interested in the molecular and cellular mechanisms underlying morphogenesis of the vertebrate brain, and in the perturbations of these processes in human diseases affecting brain development. 

We are more particularly interested in studying cell polarity processes and the dynamic localisation of intracellular cues (RNA, proteins).

  • Our first project aims at dissecting the functions of the primary cilium in brain morphogenesis using the mouse and zebrafish as model systems. Primary cilia are microtubular organelles with sensory functions, whose defects lead to human diseases called ciliopathies. We investigate the functions of Ftm/Rpgrip1l, a ciliary gene, in brain morphogenesis, cell behaviour and signalling pathways.
  • Our second project proposes to study axonal messenger RNA transport and local translation in the developing zebrafish nervous system. We query the mechanisms involved in this transport and address the biological function of this transport during nervous system development.
  • Our third project explores how cell migration coordinates with axon emergence during nervous system development. 

More...

Our group is interested in the molecular and cellular mechanisms underlying morphogenesis of the vertebrate brain, and in the perturbations of these processes in human diseases affecting brain development. We are more particularly interested in studying cell polarity processes and the dynamic localisation of intracellular cues (RNA, proteins).

  • The main project of the group aims at dissecting the functions of the primary cilium in brain morphogenesis using the mouse and zebrafish as model systems. Primary cilia are microtubular organelles with sensory functions, whose defects lead to human diseases called ciliopathies. We mainly focus on the Ftm/Rpgrip1l gene, which codes for a ciliary protein and is involved in severe ciliopathies with associated brain abnormalities. We investigate the function of this gene in brain morphogenesis, cell behaviour and signalling pathways.
  • Our second project, led by François Giudicelli, proposes to study axonal messenger RNA transport and local translation in the developing zebrafish nervous system. We query the mechanisms involved in this transport and address the biological function of this transport during nervous system development.
  • Our third project, recently initiated by Marie Breau, aims at uncovering how neuronal migration coordinates with axon emergence during nervous system development, using as a model the morphogenesis of the zebrafish olfactory placode. 

Highlights

  • Role of primary cilia in brain morphogenesis

We initiated a detailed functional analysis of Rpgrip1l in the mouse and the zebrafish. We have shown that this protein plays an essential role in mouse telencephalic patterning and in morphogenesis of the olfactory bulbs, via the formation of a repressor form of the Gli3 transcription factor. Our findings shed light on the developmental origin of olfactory bulb agenesis found in ciliopathies (Besse et al., 2011). We have also identified an original role for Rpgrip1l in planar cell polarity (PCP) establishment. Loss of function of Rpgrip1l leads to PCP defects in the mouse cochlea and in the zebrafish floor plate. We have shown that Rpgrip1l controls this process at least in part by stabilizing the core PCP protein Dishevelled (Mahuzier et al., 2012).

  • mRNA axonal transport in the developing zebrafish nervous system

We have established the zebrafish embryo as a model system to study mRNA axonal transport in nervous system development. We have demonstrated the presence of several mRNA species in axons in vivo and set up a reporter system, which allowed us to study the mechanisms of this transport (Baraban et al., 2013). 

Future directions

  • Primary cilia in brain morphogenesis

We will pursue our analysis of the diverse functions of the primary cilia in forebrain morphogenesis and in planar cell polarity, taking advantage of the mouse and zebrafish models and the multiple tools available in our lab. We want in particular to access the dynamics of PCP establishment in the zebrafish floor plate using live imaging.

  • mRNA axonal transport and local translation in vivo

Building on our results and on the tools we have developed, we will now analyse the function of axonal protein synthesis in the developing zebrafish nervous system and to decipher its underlying mechanisms. We also intend to develop tools to visualise mRNA in live animals and to detect local translation of selected mRNAs in axons. 

Collaborations

  • Ruxandra Bachmann & Stephan Neuhauss, University of Zürich, Switzerland.
  • Bénédicte Durand, Université de Lyon, France.
  • Christoph Gerhardt & Uli Rüther, Heinrich Heine University, Düsseldorf, Germany. 
  • Cecilia Moens, Fred Hutchinson Cancer Research Center, Seattle, USA. 
  • Mireille Montcouquiol, Institut Magendie, Bordeaux, France
  • Sophie Saunier, Institut Imagine, Hopital Necker, Paris, France. 
  • Thomas Theil, University of Edinburgh, UK.