Popis: |
This DOD-funded project Neural Development in tsc2-deficient zebrafish has made excellent progress over the first year of funding. We have essentially completed Task 1 of our Statement of Work with a focus on Neural Development. We have also begun Task 2 determining cell autonomous phenotypes. Using this zebrafish model of tuberous sclerosis complex, we have shown that the tsc2 gene sequence is highly conserved and also has a conserved function. The mutant tsc2vu242 allele encodes a truncated tuberin protein lacking the GAP domain. This resulted in loss of the ability to inhibit Rheb and of the TOR kinase within TOR complex 1 (TORC1). Homozygous mutant zebrafish have enlarged cells in the brain and liver. Of relevance to Task 1, forebrain neurons are poorly organized in homozygous mutants with extensive gray and white matter disorganization and ectopically positioned cells. Ongoing experiments with chimera zebrafish demonstrate that tsc2 limits TORC1 signaling in a cell-autonomous manner. However, wild-type host cells in the forebrain mislocalize in a non-cell-autonomous manner. Overall, our results demonstrate a highly conserved role of tsc2 in zebrafish during neural development. These findings are the basis for a recently accepted manuscript Kim et al. published in Disease Models and Mechanisms (Appendix). |