Loss of the epithelial transcription factor grhl3 leads to variably penetrant developmental phenotypes in zebrafish

Environmental influence is critical for embryogenesis but is significantly under-appreciated under lab conditions, which are not typically designed to robustly test environmental variability. Here, we report environmental effects on the developmental phenotype of zebrafish lacking the transcription factor Grainyhead-like 3 (grhl3), a highly conserved gene that is pivotal in epithelial barrier formation, neurulation, craniofacial development, and convergence-extension.

We had previously reported that deletion of grhl3 led to embryonic lethality by 11 h post-fertilization (hpf); however, housing these grhl3-lines in a different aquatic facility led to substantial differences in phenotypic presentation in grhl3-nullizygous (grhl3^-/-) embryos. We found that grhl3^-/- embryos presented with three distinct phenotypes, characterized by significant reductions in body length, aberrant orofacial cavity formation and craniofacial morphogenesis and impaired intestinal barrier maintenance.

Our study describes a new model of partial phenotypic penetrance in genetically identical embryos. This may serve as a valuable model system in which to understand gene-environment interactions in developmental and epithelial homeostasis.