Doctor of Philosophy

dissertationCanonical Wnt signaling plays important functions during development and in disease. In the zebrafish posterior hypothalamus, Wnt signaling is required for neuronal differentiation, but its molecular targets and physiological function are still not clear. We also do not know whether the role of Wnt signaling in hypothalamic neurogenesis and behavior is evolutionarily conserved in mammals. To address those questions, I used loss-of-Wnt genetic tools, in which Lef1 is knocked out globally in zebrafish, and conditionally in mice hypothalamus. I provided evidence supporting an indirect role of Wnt signaling in radial glial formation in the zebrafish hypothalamus. I characterized detailed cellular phenotypes in the posterior hypothalamus of zebrafish lef1 mutants and provided mechanisms underlying the cell loss phenotype. I confirmed elevated anxiety and resultant body growth retardation in both zebrafish and mice mutants. I performed ribonucleic acid (RNA) sequencing (RNA-seq) analyses on both animal models, and identified Lef1's hypothalamic functional targets, which are divergent in the two species, yet are both consistent with a function of hypothalamic Lef1 in anxiety. Together, these data suggest a conserved role for Lef1 in regulating the development of hypothalamic circuits that mediate anxiety. I believe that these genetic models may prove useful in clinical medicine for the diagnosis and treatment of anxiety-related mental disorders