We have previously shown that Wnt signaling through the transcriptional effector Lef1 is required for hypothalamic neurogenesis in zebrafish. However, the specific cellular and molecular functions of Lef1 remain unknown. We find that in zebrafish, Lef1 cell autonomously promotes the differentiation of multiple periventricular neuronal subtypes from Wnt-responsive progenitors. RNAseq analysis of zebrafish lef1 mutants supports these results, showing decreased expression of known Wnt target genes and markers for defined neuronal subtypes that regulate anxiety. Indeed, we find that zebrafish lef1 mutants display enhanced anxiety in a novel tank diving test, and gain weight more slowly than control siblings, which is consistent with enhanced anxiety. Analysis of a conditional hypothalamic Lef1 knockout mouse shows similar neurogenesis defects, as well as decreased expression of orthologous genes that are co-expressed with Lef1 in the mouse hypothalamic posterior periventricular and premammillary nuclei. Conditional Lef1 knockout mice also gain weight more slowly than controls, and we are currently testing their behavior. Finally, we have found a human LEF1 variant that is significantly enriched in Utah suicide cases, compared to equivalent control populations. Together, these data suggest a conserved role for Lef1 in regulating the development of hypothalamic circuits that mediate anxiety. We believe that our genetic models may prove useful in clinical medicine for the diagnosis and treatment of anxiety-related mental disorders.