The ancestral role of nodal signalling in breaking L/R symmetry in the vertebrate forebrain

Abstract

Left-right asymmetries in the epithalamic region of the brain are widespread across vertebrates, but their magnitude and laterality varies among species. Whether these differences reflect independent origins of forebrain asymmetries or taxa-specific diversifications of an ancient vertebrate feature remains unknown. Here we show that the catshark Scyliorhinus canicula and the lampreys Petromyzon marinus and Lampetra planeri exhibit conserved molecular asymmetries between the left and right developing habenulae. Long-term pharmacological treatments in these species show that nodal signalling is essential to their generation, rather than their directionality as in teleosts. Moreover, in contrast to zebrafish, habenular left-right differences are observed in the absence of overt asymmetry of the adjacent pineal field. These data support an ancient origin of epithalamic asymmetry, and suggest that a nodal-dependent asymmetry programme operated in the forebrain of ancestral vertebrates before evolving into a variable trait in bony fish.

Nodal signalling and asymmetry of the nervous system

“…In the previous section, we already mentioned the example of habenular asymmetries of lampreys, catshark and zebrafish in which Nodal works as asymmetry inducer (figure 3a-c). These asymmetries are PpO-independent in the three species, although by different ontogenic mechanisms: (i) catsharks do not form a recognizable PpO [22], (ii) lampreys do have a midline PpO, but habenular asymmetries develop before the PpO is formed [22] and (iii) zebrafish have an asymmetrically positioned PpO but a sub-type of habenular asymmetries develops even in the absence of PpO, i.e. when the PpO is physically ablated [40,41,52].…”

“…Evidence that such a modification might have occurred comes from studies showing that the onset of PpO connectivity is heterochronic when comparing the ontogeny of epithalamic asymmetry among related teleost species [18,73]. The fact that in the lamprey the PpO only develops after asymmetries of the Hb are anatomically distinguishable [22] only argues against a possible direct control of Nodal on the asymmetric projection of the PpO in this species, but is coherent with the idea that this effect can be mediated by the asymmetry of the Hb. Therefore, we explicitly propose that Hb-dependent PpO asymmetries played a key role in the evolution of epithalamic asymmetries and that these types of asymmetries might be present in modern species.…”

“…We have already mentioned the example of the ascidian ocellus photoreceptor, which can be regarded as a bilaterally paired structure concerning the bilateral position of competent cells sensitive to Rx gene function [13]. Another example of a bilaterally paired structure that displays isomerism when Nodal becomes absent or bilateral is the Hb of lampreys and catsharks (figure 3a,b) [22], and for some types of asymmetries the Hb of zebrafish (i.e. parapineal-independent asymmetries; see §5 and figures 3c and 4a) [52].…”

“…The proposal of an antisymmetric control of PpO asymmetric migration mediated by FGF is an example of such mechanism, which provides support to the idea that epithalamic asymmetry evolved along the two-step route. However, recent developmental and evolutionary information revealing the ancestral condition of PpO-independent habenular asymmetries [22] prompts us to re-evaluate the existing hypotheses about the evolution of epithalamic asymmetry [14,51]. rstb.royalsocietypublishing.org Phil.…”

“…Asymmetries comprise the bilaterally paired habenular nuclei (Hb) and some midline components of the pineal complex, and show significant variations in morphology, and in the extent and sidedness of L-R differences among species [14,[17][18][19]. Importantly, developmental studies in fishes reveal that epithalamic asymmetry is preceded and controlled by the asymmetric expression of Nodal (figure 1c-e) [20][21][22] (see details below in §4). In echinoderms, Nodal is expressed in the right ciliary band, specifically in a cluster of prospective neurons located on the right side of the apical tuft (figure 1f ) [23].…”