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Show 113 zebrafish and mice, our animal models will still have clinical applications because Lef1's hypothalamic targets in zebrafish and mice are either proven (e.g., 5-HT-related drugs) or will likely to be proven useful in treating anxiety or depression associated diseases. One can screen for anxiolytic drugs with our zebrafish or mouse models. If there is a depressionrelated phenotype in our animals, one can also screen antidepressants in our models. In fact, I am particular excited about using the zebrafish model to screen anxiolytics. I showed that fish at 16 dpf can robustly display an anxiety-like phenotype in a novel tank diving test, which is sensitive enough to detect an anxiogenic-like phenotype in our zebrafish mutant. With larval zebrafish, one could screen drugs in a high throughput manner, and screened drugs can be tested in mice models and in human clinical trials later. Although the anxiety phenotype of our zebrafish germline finless lef1 mutant can be detected by a novel tank diving test, it would still be a priority to make a hypothalamus-specific conditional zebrafish mutant for behavioral validation and potential drug screening. However, different Lef1 targets in zebrafish and mice hypothalamus suggest that zebrafish may not be the ideal model system to study the development of the anxiety circuity. More work is warranted to determine whether this evolutionary divergence is specific to hypothalamic Lef1-dependent Wnt signaling. 4.3 Stress response 4.3.1 Overview We found reduced body growth and elevated anxiety in both zebrafish and mice mutants lacking Lef1, and hypothesize that the reduced body growth is secondary to elevated anxiety. Given the large body of literature characterizing the mouse hypothalamic |
