Bulk RNA-sequencing of pooled 26 hpf maternal-zygotic MZ osgep G177A homozygote

Mouse Osgep knockouts had significantly shorter cortex lengths, widths and cortex–midbrain midline lengths. A renal phenotype was not observed in either knockout model, possibly due to early lethality masking renal involvement in older animals. Based on human-genetic data, we generated a zebrafish osgep G177A knock-in mutant. osgepG177A/G177A larvae have smaller eyes and heads relative to wildtype.

The mutants have growth defects and about 70% of them die during the first 4-5 weeks post-fertilization. We determined that the p53 pathway is activated in osgepG177A/G177A embryos and elevates apoptosis levels. However, loss of tp53 does not rescue the phenotypes or survival of osgep mutants.

RNA-sequencing of single wildtype and osgepG177A/G177A larvae identified >1000 differentially-expressed genes. Up-regulated genes were associated with protein folding, endoplasmic reticulum, RNA processing/maturation and ribosome biogenesis. Down-regulated genes were strongly enriched among translation-related, developmental, immune and hematopoietic terms, inflammatory response as well as Ribosome, Proteasome, Ferroptosis, Apoptosis and Oxidative Phosphorylation pathways.

Maternal-zygotic (MZ) osgepG177A/G177A embryos generated from the surviving zygotic mutants exhibit dramatically exacerbated phenotypes with dramatically increased activations of p53 pathway and various Unfolded Protein Response (UPR) genes. Loss of tp53 in osgepG177A/G177A MZ embryos further worsened their phenotypes and did not alter UPR gene up-regulation.