Phenotype of the zebrafish masterblind (mbl) mutant is dependent on genetic background

The zebrafish masterblind (mbl) mutant is characterized by the lack of olfactory placodes and optic vesicles, reduced telencephalon, an expanded epiphysis (Heisenberg et al. [1996] Development 123:191-203), and enlarged jaw. To understand the cellular events giving rise to the olfactory placode defect of this mutant, we examined the expression pattern of the distal-less-3 (dlx3) gene in mbl. In the mutant, dlx3, which is normally expressed in the developing nose and ear, showed reduced expression in the olfactory placode field, but normal expression in the developing ear. To determine whether the loss of dlx3 expression was due to cell loss, we assayed cell death by using TUNEL labeling. Although cell death in the mutant was not concentrated in the region of dlx3 expression, there was increased cell death in the forebrain, epiphysis, and jaw region, as compared with that in wild-type controls. This cell death phenotype was cyclical in nature, showing an increase and decrease in cell death on a roughly 24-hr cycle. Further analysis showed that this cyclical phenotype was specific to the genetic background. The severity of the mbl phenotype, including cell death, expanded epiphysis, and enlarged jaw, decreased when the mutation was moved from the original "TL" background to the "AB" background. Thus, the severity of developmental defects in the mbl mutant is strongly dependent on genetic background. We examined the contribution of cell death to the morphologic defects of mbl by blocking cell death by using zVADfmk, a known caspase inhibitor. We found that this treatment partially rescued the expanded jaw defect and that this rescue was dependent on the genetic background. Therefore, the mbl mutant phenotypes result, in part, from genetic background effects that alter the pattern of programmed cell death early in development.