While innate behaviors are conserved throughout the animal kingdom, it is unknown whether common signaling pathways regulate the development of neuronal populations mediating these behaviors in diverse organisms. Here, we demonstrate that the Wnt/ß-catenin effector Lef1 is required for the differentiation of anxiolytic hypothalamic neurons in zebrafish and mice, although the identity of Lef1-dependent genes and neurons differ between these 2 species. We further show that zebrafish and Drosophila have common Lef1-dependent gene expression in their respective neuroendocrine organs, consistent with a conserved pathway that has diverged in the mouse. Finally, orthologs of Lef1-dependent genes from both zebrafish and mouse show highly correlated hypothalamic expression in marmosets and humans, suggesting co-regulation of 2 parallel anxiolytic pathways in primates. These findings demonstrate that during evolution, a transcription factor can act through multiple mechanisms to generate a common behavioral output, and that Lef1 regulates circuit development that is fundamentally important for mediating anxiety in a wide variety of animal species.

虽然先天行为在整个动物界都是保守的，但尚不清楚共同的信号通路是否调节不同生物体中介导这些行为的神经元群的发育。在这里，我们证明 Wnt/ß-连环蛋白效应器 Lef1 是斑马鱼和小鼠抗焦虑下丘脑神经元分化所必需的，尽管这两个物种之间 Lef1 依赖性基因和神经元的身份不同。我们进一步表明，斑马鱼和果蝇在各自的神经内分泌器官中具有共同的 Lef1 依赖性基因表达，这与小鼠中存在分歧的保守途径一致。最后，来自斑马鱼和小鼠的 Lef1 依赖性基因的直向同源物在狨猴和人类中显示出高度相关的下丘脑表达，表明灵长类动物中 2 个平行的抗焦虑途径的共同调节。这些发现表明，在进化过程中，转录因子可以通过多种机制发挥作用，产生共同的行为输出，并且 Lef1 调节回路发育，这对于调节多种动物物种的焦虑至关重要。