Wnt/Axin1/β-Catenin Signaling Regulates Asymmetric Nodal Activation, Elaboration, and Concordance of CNS Asymmetries

Abstract

SummaryNodal activity in the left lateral plate mesoderm (LPM) is required to activate left-sided Nodal signaling in the epithalamic region of the zebrafish forebrain. Epithalamic Nodal signaling subsequently determines the laterality of neuroanatomical asymmetries. We show that overactivation of Wnt/Axin1/β-catenin signaling during late gastrulation leads to bilateral epithalamic expression of Nodal pathway genes independently of LPM Nodal signaling. This is consistent with a model whereby epithalamic Nodal signaling is normally bilaterally repressed, with Nodal signaling from the LPM unilaterally alleviating repression. We suggest that Wnt signaling regulates the establishment of the bilateral repression. We identify a second role for the Wnt pathway in the left/right regulation of LPM Nodal pathway gene expression, and finally, we show that at later stages Axin1 is required for the elaboration of concordant neuroanatomical asymmetries.

Zebrafish and medaka: model organisms for a comparative developmental approach of brain asymmetry

“…In zebrafish larvae, efferent connectivity from left and right habenular nuclei forms distinct and segregated ring-shaped domains within dorsal and ventral regions of the IPN, respectively (figure 1a(vi),(vii); Aizawa et al 2005;Gamse et al 2005;Bianco et al 2008). A similar pattern of habenular efferent connectivity is observed in the larval IPN of medaka (see figure 1b (vi),(vii); Carl et al 2007). However, the cross-sectional area of the central fibre-free region of IPN rings, compared with the crosssectional area of the entire IPN appears relatively larger in medaka (26.7G3% of total IPN, nZ3 embryos, meanGs.d.)…”

“…For example, the nodal inhibitor lefty1 (Dr-lefty1) and the downstream transcriptional effector pitx2c (Dr-pitx2c) define restricted dorsal domains of expression in the left side of the neural tube, posterior to the lateral flexure of the diencephalic ventricle (figure 1a(i),(ii)). Recent reports in medaka have shown that Ol-lefty (Carl et al 2007;Soroldoni et al 2007) and Ol-pitx2 (Jaszczyszyn et al 2007) also display asymmetric expression in the dorsal diencephalon, and a close examination indicates that the extent and topology of expression of these genes are similar to zebrafish (compare figure 1a(i),b(i) and a(ii),b(ii)).…”

“…(e.g. Lynn Lamoreux et al 2005;Gajewski et al 2006;Carl et al 2007). The present study brings additional support to this notion, offers new tools for time comparison between these species and provides novel comparative data and hypotheses to start addressing the ontogenic mechanisms that explain interspecies variations of epithalamic asymmetry.…”

“…Such independence in the developmental control of asymmetry and laterality makes the epithalamus of zebrafish an attractive vertebrate model to study the ontogenic (genetic and epigenetic) mechanisms that underlie directional asymmetries, in which most individuals are asymmetrical in the same direction within the population (Van Valen 1962). Second, laterality of epithalamic asymmetry is coupled to laterality of visceral asymmetry (Concha et al 2000;Long et al 2003;Carl et al 2007) in contrast to other structural and functional asymmetries of the vertebrate brain, e.g. asymmetries associated to speech and handedness (Torgersen 1950;Kennedy et al 1999;Tanaka et al 1999).…”

Nodal signalling and asymmetry of the nervous system

“…This first morphological asymmetry of the zebrafish epithalamus is followed by the development of prominent structural and functional asymmetries of the Hb ( figure 4a(v-viii)) [40,42]. Experiments of PpO ablation and mutant conditions that delay the onset of PpO asymmetric translocation reveal a requirement of an asymmetrically positioned PpO for the subsequent development of a sub-type of asymmetries in the Hb ( figure 4a(iii)) [40][41][42]58]. These asymmetries result from L-R differences in cell fate decisions towards two main neuronal identities, and it is possible that the PpO modulates these fate decisions as well as the timing of asymmetric habenular neurogenesis by acting on the Notch and Wnt signalling pathways [43,44].…”