Diencephalon of a 3.5-day-old Zebrafish embryo. Courtesy of Stephen Wilson, University College London, London, UK.

Functional asymmetries of the vertebrate brain, such as the localization of speech areas to the left hemisphere in humans, have been well documented. Indeed, although vertebrate brains are largely symmetrical, neuroanatomical and cognitive left–right differences have been identified in all species that have been examined. However, it has remained uncertain how these asymmetries arise during devlopment. Evidence for genetic control of forebrain asymmetry is now emerging from studies on the zebrafish brain, which has several features that show overt lateral asymmetry. Research has focused on two diencephalic structures; the habenular nucleus, which is larger on the left side than the right, and the parapineal organ, which is located to the left of the midline.

Concha et al. describe the effects of disrupting Nodal signalling on the development of these two structures. The Nodal pathway is conserved between species and is important for the generation of left–right asymmetry in the heart and viscera. The nodal homologue cyclops (cyc) and the homeobox gene pitx2 are normally expressed only on the left side of the developing diencephalon. The authors obtained evidence that early activity of the Cyclops cofactor, one-eyed pinhead (Oep), leads to repression of cyc and pitx2 on both sides of the diencephalon, whereas later Oep-dependent signalling, combined with activity of the transcription factor gene Schmalspur (Sur), overcomes this repression on the left side. They showed that embryos mutant for sur or lacking late Oep function did not express cyc and pitx2 in the diencephalon. Conversely, ablation of the midline results in bilateral expression of these genes, indicating that signals from this tissue are required for their repression. In both cases, the diencephalon still developed asymmetrically, but the laterality of the asymmetry became random.

So, Nodal signalling does not seem to be essential for asymmetric brain development per se, but it determines the direction of the asymmetry. Further experiments will elucidate the mechanisms that initiate the development of brain asymmetry, and show whether anatomical and functional asymmetries are influenced by common factors.