GSK-3 Activity Is Critical for the Orientation of the Cortical Microtubules and the Dorsoventral Axis Determination in Zebrafish Embryos

The formation of dorsal-ventral (D–V) axis is the earliest event that breaks the radial symmetry and determines the bilateral body plan of a vertebrate embryo, however, the maternal control of this process is not fully understood. Here, we discovered a new dorsalizing window of acute lithium treatment, which covers only less than 10 minutes after fertilization. Lithium treatment in this window was not able to reverse the ventralized phenotype in tokkeabi (tkk) mutant embryos, and its dorsalizing activity on wild-type embryos was inhibited by nocodazole co-treatment. These evidences indicate that the underlying mechanism is independent of a direct activation of Wnt/β-catenin signaling, but depends on the upstream level of the microtubule mediated dorsal determinant transport. In order to identify the target of lithium in this newly discovered sensitive window, GSK-3 inhibitor IX as well as the IMPase inhibitor L690, 330 treatments were performed. We found that only GSK-3 inhibitor IX treatment mimicked the lithium treatment in the dorsalizing activity. Further study showed that the parallel pattern of cortical microtubules in the vegetal pole region and the directed migration of the Wnt8a mRNA were randomized by either lithium or GSK-3 inhibitor IX treatment. These results thus revealed an early and critical role of GSK-3 activity that regulates the orientation of the cortical microtubules and the directed transport of the dorsal determinants in zebrafish embryos

Convergent functional genomic studies of omega-3 fatty acids in stress reactivity, bipolar disorder and alcoholism

Omega-3 fatty acids have been proposed as an adjuvant treatment option in psychiatric disorders. Given their other health benefits and their relative lack of toxicity, teratogenicity and side effects, they may be particularly useful in children and in females of child-bearing age, especially during pregnancy and postpartum. A comprehensive mechanistic understanding of their effects is needed. Here we report translational studies demonstrating the phenotypic normalization and gene expression effects of dietary omega-3 fatty acids, specifically docosahexaenoic acid (DHA), in a stress-reactive knockout mouse model of bipolar disorder and co-morbid alcoholism, using a bioinformatic convergent functional genomics approach integrating animal model and human data to prioritize disease-relevant genes. Additionally, to validate at a behavioral level the novel observed effects on decreasing alcohol consumption, we also tested the effects of DHA in an independent animal model, alcohol-preferring (P) rats, a well-established animal model of alcoholism. Our studies uncover sex differences, brain region-specific effects and blood biomarkers that may underpin the effects of DHA. Of note, DHA modulates some of the same genes targeted by current psychotropic medications, as well as increases myelin-related gene expression. Myelin-related gene expression decrease is a common, if nonspecific, denominator of neuropsychiatric disorders. In conclusion, our work supports the potential utility of omega-3 fatty acids, specifically DHA, for a spectrum of psychiatric disorders such as stress disorders, bipolar disorder, alcoholism and beyond