Structural and functional nervous system asymmetries are conserved throughout the animal kingdom and have been shown to impact cognition and behavior. Despite their prevalence, our understanding of the genetic bases for the development of brain asymmetries is still sparse.
One of the most amenable structures in which to study developmental mechanisms underlying central nervous system asymmetries is the epithalamus. In zebrafish, this structure is composed of the medially positioned pineal complex and the bilateral asymmetric habenular nuclei.
We isolated the rorschach (rch) mutant through a mutagenesis screen to identify mutations disrupting habenular asymmetry. Mutant embryos display left-isomerized symmetric habenula yet viscera asymmetries are unaffected. Positional cloning has shown that rch mutants have a V1122D substitution in the cache domain containing 1 gene which encodes a novel type I transmembrane protein. The lesion occurs in the gene’s single transmembrane domain and disrupts protein localization.
We have performed a screen to identify binding partners for Cachd1 and found that it physically interacts with Frizzled receptors – key components of the Wnt signaling pathway. This is consistent with previous studies showing Wnt signaling has a pivotal role in the elaboration of asymmetries within the habenular nuclei. Temporal and spatial activation of a reporter for β-catenin dependent transcription and expression of axin2, a bona-fide Wnt target gene, are affected in the developing diencephalon of rch mutants, while epistasis studies show that Cachd1 acts upstream of Axin1.
Taken together these findings suggest that Cachd1 modulates the activation status of Wnt signaling in habenula progenitors to regulate allocation of left-right character to habenular neurons.