# The Role of Retrotransposon Activity in Mammalian Pre-Implantation Development

> **NIH NIH R00** · UNIVERSITY OF PENNSYLVANIA · 2024 · $246,373

## Abstract

Abstract
Nearly half of both human and mouse genomes originate from ancient retroviral integrations. While silenced in
nearly all cells, retrotransposon reactivation is a recognized phenomenon occurring in preimplantation embryos.
In a handful of reports, disruption of retrotransposon family expression resulted in embryonic lethality, suggesting
essential functions, but the cause of this is completely unknown. The majority of retrotransposons have been
inactivated through mutation. Still, many retain regulatory and structural features of intact elements, with rare
reports of retrotransposon influence of nearby genes. The highly repetitive nature of retrotransposons has made
studying their individual functions difficult, however re-analysis of single cell pre-implantation mouse embryos
revealed striking levels of dynamically expressed retrotransposon families. Most retrotransposons are only active
during defined windows of time, sometimes spanning a single cell division. Interestingly, a subset of these loci
are spliced with nearby protein coding genes, generating “chimeric transcripts” that form hundreds of novel
embryonic specific promoters, exons and polyadenylation sites. As a proof-of-principle, a highly efficient
electroporation based CRISPR embryo editing method developed in the lab was used to generate
retrotransposon deletions of two chimeric promoters. The deletion of the MT2B1 promoter driving Rpl41 results
in delayed global translation, causing stress induced arrest. The second, deletion of the MT2C_Mm promoter of
the cell cycle regulator Cdk2ap1, results in small litters, physical abnormalities, embryo spacing, crowding and
implantation into unsuitable uterine sites, reminiscent of the human pregnancy complications placenta previa,
accreta and potentially pre-eclampsia. Thus, the applicant hypothesizes that retrotransposon reactivation and
transcript chimerism in preimplantation is essential for early embryonic development and implantation. During
the K99 phase, the applicant will train in three cutting edge technologies: automated live cell spinning disk
confocal imaging, single cell/embryo Western Blot with Dr. Amy Herr and ultra-low input Ribosome Profiling of
Embryos with Dr. Nicholas Ingolia. These collaborations and additional coursework will help the applicant master
the techniques needed for long term academic and career goals. To this end, Aim1 will serve to understand the
cellular cause of the implantation defects of the M2TC_Mm:CKD2ap1 deletion, offering insight into novel
explanations for related human pregnancy issues. Aim2 will work to elucidate the role of M2TB1:Rpl41 in global
translation as well as to gain insight into the oxidative and metabolic needs of the developing embryo. Aims 1
and 2 will be completed during the K99 phase. During the R00 phase, Aim 3 will work to determine the extent of
retrotransposon influence on the preimplantation embryo. Together with Dr. Davide Risso, parallel analysis of
the embryo ribos...

## Key facts

- **NIH application ID:** 10839983
- **Project number:** 5R00HD096108-06
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Andrew Joseph Modzelewski
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $246,373
- **Award type:** 5
- **Project period:** 2022-03-18 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10839983

## Citation

> US National Institutes of Health, RePORTER application 10839983, The Role of Retrotransposon Activity in Mammalian Pre-Implantation Development (5R00HD096108-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10839983. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*