Establishing left-right asymmetry brain asymmetry

The left and right hemispheres of our brain display structural and molecular left- right (LR) asymmetries that correlate with their functional specialization in specific cognitive tasks. Despite the widespread representation of brain lateralisation across evolution, our knowledge of how anatomical asymmetries are established is still poor. We are using the zebrafish epithalamus as a model to study the cellular and molecular basis of brain LR asymmetry (for review see Roussigné et al., 2012 and Duboc et al, 2015).

LR asymmetry in the epithalamus is established via a stepwise sequence of interactions between the left presumptive habenula and the migrating parapineal. Studies have shown that handedness of these asymmetry are biased by unilateral Nodal signalling. We have shown a L/R asymmetry in the pool of neurog1+ habenular progenitors and that this asymmetry is compromised in the absence of Nodal signalling (Roussigné et al., 2009) ; more recent results from the group indicate that Nodal imposes this neurogenetic asymmetry via the transcription factor Pitx2c (Garric et al., in prep). In the absence of Nodal signalling, however, habenular neurogenesis is not absent suggesting that Nodal/Pitx2c influences a generic neurogenesis pathway. We have unpublished evidence that this pathway requires Sonic hedghog signalling, Pax6 and ultimately the redundant activities of Neurog1 and NeuroD4 (Halluin et al., in prep). Finally, we have been able to show that abrogating the function of Pitx2c leads to the right habenula adopting aspects of left character, and to an increase in parapineal cell numbers. These results suggest that restricting parapineal cell number is crucial for the correct elaboration of epithalamic asymmetry and that Pitx2c plays a role in this process (Garric et al., 2014).

Ongoing works by Myriam Roussigne in the lab aim to understand how the parapineal cells collectively migrate to the left.  It has been shown that, in Fgf8 mutant embryos, the parapineal often fails to migrate away from the midline (Regan et al., 2009). Thus, while Nodal/TGFb signaling imposes a left bias to parapineal laterality, Fgf8 factor is the signal required for parapineal cells to migrate. However, the molecular and cellular mechanisms by which Fgf8 promotes parapineal migration and by which Nodal biases this Fgf8-dependant parapineal migration are completely unclear. By imaging the dynamic of Fgf activation in real time, we observed that Fgf signaling is activated focally in only a few parapineal cells that are usually located at the leading edge of the PP prior and during its migration. We are currently developing different approaches to address whether the focal activation of Fgf signalling in few parapineal cells is sufficient to promote the migration of the whole parapineal organ and to understand how Nodal signaling influences Fgf dependant parapineal migration to impose a left orientation. This project is part of a close collaboration with Steve Wilson lab (UCL, London UK) and Matthias Carl (Mannheim, Germany)

Véronique Duboc

Advancement of our understanding of developmental processes rely heavily on the identification of new pathways or regulators.  We are using unbiased approaches based on high throughput sequencing technics to describe the changes in zebrafish brain transcriptome during its development. By comparison between wild type embryos at relevant stages and/or different mutant contexts, we aim at identifying new actors of brain left-right asymmetries.