Origin and Diversification of Brain Asymmetries in Vertebrates – AsymmetricBrain

A central goal of evolutionary developmental biology is to understand how functional anatomical structures and underlying developmental mechanisms have concomitantly evolved. Progress in large-scale genomic approaches has paved the way for the exploration of this question with an unprecedented resolution at the microevolutionary scale. In view of these advances, and in light of our ever-growing knowledge of developmental mechanisms in classical model organisms, it is perhaps surprising that at the macroevolutionary scale, the rules that constrain the basic architecture of developmental gene regulatory networks or promote their plasticity remain poorly understood.
Morphological diversification of certain brain regions in the vertebrate lineage offers attractive biological systems for a more systematic study of the evolutionary modulation of developmental mechanisms at a macroevolutionary level. The establishment of left-right (LR) asymmetry in the epithalamus, a dorsal subdivision of the diencephalon composed of the pineal complex and the habenular nuclei, is a particularly appealing system in this respect; the epithalamus represents the only brain structure to exhibit conspicuous LR asymmetries across all major vertebrate phyla. The collective efforts of groups in the United States, Japan and Europe have laid down a solid, if incomplete framework concerning the molecular and cellular mechanisms employed for the development of this asymmetry in a reference model organism, the zebrafish. From these studies, two major developmental events have been described. The first involves the parapineal organ, a small group of neurons situated on the left side of the epithalamus that plays a key instructive role in the elaboration of left habenular identity. The second, uncovered by the Blader group, involves an early neurogenetic asymmetry between the habenulae that requires the Nodal signalling pathway but that is not essential for the formation of definitive habenular asymmetries. The Mazan group has recently addressed whether these mechanisms are also employed in two non-conventional vertebrate models, the lamprey and the catshark. Their results indicate that while no evidence for conservation of the zebrafish parapineal dependent mechanism is found in these species, Nodal signalling is necessary for the formation of epithalamic asymmetries in both the lamprey and the catshark; abrogation of pathway activity in either species results in right habenular isomerism in a manner similar to parapineal ablation in the zebrafish. Thus, different species use different strategies for establishing epithalamic asymmetry.

Our project has two major objectives:
(1) to unravel the ancestral mechanisms controlling the establishment of LR asymmetries in the epithalamus of the lamprey and catshark.
(2) to decipher the molecular and cellular origin of the novel parapineal dependent mechanism that has arisen during the course of teleost evolution.

Our strategy for achieving these objectives will employ genome-wide RNA sequencing, including RNA tomography, coupled with functional analysis based on CRISPR/Cas9 genome editing. In this manner, we will uncover the gene regulatory networks underlying the development of epithalamic asymmetry in these species. Subsequent comparison of data between species will indicate to what extent ancestral mechanisms have been superseded by novel ones and whether these innovations represent subtle or drastic changes at either the molecular or cellular level. Our recognized expertise, as well as a fruitful network of world-class collaborations, supports the feasibility of this proposal and places us in an excellent position to succeed in this challenging task. Results from our work will have important implications, at both evolutionary and mechanistic levels, on our understanding of the formation of a brain structure known to play a key role in certain adaptive behaviours.