FGF activity asymmetrically regulates the timing of habenular neurogenesis in a Nodal-dependent manner

The highly conserved habenular nuclei in the vertebrate epithalamus function as an integrating center that relaying information between the forebrain and the brain stem. These nuclei play crucial roles in modulating a broad variety of cognitive behaviors. Moreover, habenular nuclei has also attracted interest as a model for brain asymmetry, since many vertebrates exhibit left-right differences in habenular size and neural circuitry. Left-right (L/R) asymmetry is a shared feature of the central nervous system in vertebrates. Despite its prevalence and functional significance, few studies have addressed the molecular bases for the generation of the asymmetric brain structure, perhaps due to the absence of genetically accessible model animals showing robust brain asymmetry. Previous studies on zebrafish epithalamus demonstrated that Nodal signaling directs the habenular asymmetry during the early stages of development by biasing the neurogenesis on the left-side. Here, we discover a novel regulatory module involving asymmetric activation of FGF signaling that determines the timing of habenular neurogenesis by regulating cell-cycle progression of neuronal progenitors, which seamlessly integrates the L/R patterning driven by Nodal and the spatiotemporal patterning of habenular neurons.