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

Cell. 2021 Oct 28;184(22):5541-5558.e22. doi: 10.1016/j.cell.2021.09.021. Epub 2021 Oct 12.

Abstract

Retrotransposons mediate gene regulation in important developmental and pathological processes. Here, we characterized the transient retrotransposon induction during preimplantation development of eight mammals. Induced retrotransposons exhibit similar preimplantation profiles across species, conferring gene regulatory activities, particularly through long terminal repeat (LTR) retrotransposon promoters. A mouse-specific MT2B2 retrotransposon promoter generates an N-terminally truncated Cdk2ap1ΔN that peaks in preimplantation embryos and promotes proliferation. In contrast, the canonical Cdk2ap1 peaks in mid-gestation and represses cell proliferation. This MT2B2 promoter, whose deletion abolishes Cdk2ap1ΔN production, reduces cell proliferation and impairs embryo implantation, is developmentally essential. Intriguingly, Cdk2ap1ΔN is evolutionarily conserved in sequence and function yet is driven by different promoters across mammals. The distinct preimplantation Cdk2ap1ΔN expression in each mammalian species correlates with the duration of its 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.

Keywords: Cdk2; Cdk2ap1; cell proliferation; implantation; mammals; mouse; preimplantation embryos; promoters; retrotransposons; transposons.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Blastocyst / metabolism
  • Cell Proliferation
  • Conserved Sequence*
  • Embryonic Development / genetics*
  • Evolution, Molecular
  • Female
  • Gene Expression Regulation, Developmental
  • Human Embryonic Stem Cells / metabolism
  • Humans
  • Mammals / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • Promoter Regions, Genetic
  • Protein Isoforms / metabolism
  • Protein Kinases / metabolism*
  • Retroelements / genetics*
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Protein Isoforms
  • Retroelements
  • Tumor Suppressor Proteins
  • Protein Kinases
  • Cdk2ap1 protein, mouse