HALPERN, ME*; KUAN, YS; SANTHAKUMAR, K; GAMSE, JT; Carnegie Institution; Carnegie Institution; Carnegie Institution; Vanderbilt University: Left-Right Asymmetry in the Zebrafish Brain

In the human cortex, the left hemisphere functions differently from the right. How this specialization arises and the corresponding anatomical substrates are poorly understood. The zebrafish epithalamus is a valuable model for exploring how L-R differences form in a vertebrate brain. We have characterized genes expressed asymmetrically in this region of the developing brain and examined regulation of such L-R differences. A homologue of nodal, which encodes a TGF-beta signal that mediates asymmetric development of the heart and visceral organs, is expressed in the left side of the pineal organ. There it sets the directionality of asymmetry, generating L-R bias at the individual and populational level. To the left of the pineal lies the parapineal, where it influences the adjacent brain nucleus, the left habenula, to develop differently from the right habenula. Loss of nodal causes L�R randomization in parapineal position and habenular laterality. Ablation of the parapineal blocks laterality and both habenulae develop similarly. Asymmetry of the habenulae extends to their efferent projections and innervation of the midbrain target, the interpeduncular nucleus/ Left habenular neurons project along the entire dorsoventral extent of the target, while right habenular neurons project only ventrally. The stereotypic projection pattern is disrupted by parapineal loss. We identified mutations that affect habenular development specifically, left-right differences, or differentiation of habenular cholinergic neurons. Our results reveal a hierarchy of genetic and cellular interactions underlying L-R specification of the dorsal diencephalon and formation of neuronal midbrain connections.