A species-specific retrotransposon drives a conserved Cdk2ap1 isoform essential for preimplantation development

Retrotransposons mediate gene regulation in multiple developmental and pathological processes. Here, we characterized the transient retrotransposon induction in preimplantation development of eight mammalian species. While species-specific in sequences, induced retrotransposons exhibit a similar preimplantation profile, conferring gene regulatory activities particularly through LTR retrotransposon promoters. We investigated a mouse-specific MT2B2 retrotransposon promoter, which generates an N-terminally truncated, preimplantation-specific Cdk2ap1 ΔN isoform to promote cell proliferation. Cdk2ap1 ΔN functionally contrasts to the canonical Cdk2ap1 , which represses cell proliferation and peaks in mid-gestation stage. The mouse-specific MT2B2 element is developmentally essential, as its deletion abolishes Cdk2ap1 ΔN , reduces cell proliferation and impairs embryo implantation. Intriguingly, Cdk2ap1 Δ N is evolutionarily conserved across mammals, driven by species-specific promoters. The distinct preimplantation Cdk2ap1 Δ N expression across different mammalian species correlates with their different duration in preimplantation development. Hence, species-specific transposon promoters can yield evolutionarily conserved, alternative protein isoforms, bestowing them with new functions and species-specific expression to govern essential biological divergence. One Sentence Summary In mammalian preimplantation embryos, retrotransposon promoters generate conserved gene isoforms, confer species-specific expression, and perform essential developmental functions.