Loss of CMTR1 leads to gastrulation failure and early embryonic lethality.

Cap Methyltransferase 1 (CMTR1) facilitates the addition of a 5' methyl cap on eukaryotic mRNA molecules. Using a knock-out (KO) allele, we demonstrate that CMTR1plays an essential role during gastrulation. In the absence of CMTR1, mutant embryos undergo early lethality, arresting prior to organogenesis with severe developmental delay apparent at E7.5. Multiple molecular approaches indicate significant disruptions in the ability of the CMTR1-KO embryo to form the three primary germ layers - likely driving the observed gastrulation failure. Our analysis of CMTR1 has revealed an unexpected sexually dimorphic phenotype. Female CMTR1 null embryos are more severely delayed and have increased differentially expressed genes compared to male mutants; presumably causing a variety of downstream consequences and a more severe developmental phenotype. Importantly, we do not observe defects in X-inactivation, suggesting that there are unidentified sexually dimorphic mechanisms active during early embryonic stages, prior to the onset of known differences between XX and XY embryos. In sum, we illustrate the necessity of CMTR1 during embryonic development and reveal novel insights into differences in gene regulation pathways between sexes prior to organogenesis.