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Abstract

Brain asymmetries are a conserved feature of the vertebrate nervous systems that allows an efficient processing of complex neuronal tasks. Given that alterations in asymmetrically formed areas of the human brain can have devastating consequences it is surprising that the genetic basis underlying their development is still poorly understood. In the zebrafish epithalamus, medial and lateral neurons of the habenulae are differentially distributed on the left and right side of the brain. Recent advances shed light on signaling pathways involved in the establishment of asymmetric habenulae. However, the underlying mechanisms and epistatic relationships between them are unclear. This study reveals that Tcf7l2 is a key component of habenular asymmetry establishment. In its absence the habenulae develop symmetric neuronal specification as habenular progenitors differentiate mainly into lateral neurons on both sides of the brain. Interestingly, Tcf7l2 is expressed asymmetrically in habenular precursor cells. The data obtained are consistent with a model by which Tcf7l2 mediated Wnt/beta-catenin signaling switches the differentiation program of precursor cells and promotes medial habenula cell fate. On the left side, this activity is suppressed by signals derived from the adjacent parapineal cells, which results in continued generation of lateral habenula neurons. Thus, a combination of parapineal and Tcf7l2 signals can promote the asymmetric habenular organization.