Neurogenic Determinants of Left-Right Brain Asymmetry: Developmental Investigations of the Zebrafish Habenular Nuclei

Abstract

Left-Right asymmetry of the CNS is a highly conserved feature across vertebrate classes. Asymmetry is manifest at the levels of function and connectivity. But the neural correlates of these asymmetries and their developmental underpinnings are just beginning to be explored. The zebrafish habenular nuclei have functional as well as neuronal asymmetries and offer a molecularly manipulable and highly visualizable model to studying the cellular and developmental origins of CNS left-right asymmetry. Here I report an evolving developmental network that regulates the timing of habenular neurogenesis. This network involved environmental and endocrine cues (light and melatonin), morphogenetic pathways (FGF and Nodal) and several neurogenic genes (dbx1b, lhx9, kip2 and her6). These components act as a temporal ‘neurogenic gate,’ dictating the onset of neurogenesis. This neurogenic gate is regulated asymmetrically – acting first in the left habenula driving earlier neurogenesis there – and impacts neuronal cell type specification. Together these findings deepen our understanding of the molecular mechanisms that drive neural fate specification and how these components can give rise to left-right asymmetry in the CNS.