Aberrant Uterine Folding in Mice Disrupts Implantation Chamber Formation and Alignment of Embryo-Uterine Axes

Authors

Manoj K Madhavan
Francesco J DeMayo
John P Lydon
Niraj R Joshi
Asgerally T Fazleabas
Ripla Arora

Publication Date

6-1-2022

Journal

Development

DOI

10.1242/dev.200300

PMID

35575097

PMCID

PMC9245188

PubMedCentral® Posted Date

6-13-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Embryo Implantation, Embryo, Mammalian, Epithelium, Female, Horses, Humans, Mammals, Mice, Pregnancy, Uterus, Uterine folds, Implantation chamber, Embryo-uterine orientation, Embryo morphogenesis, WNT5A, RBPJ

Abstract

The uterine luminal epithelium folds characteristically in mammals, including humans, horses and rodents. Improper uterine folding in horses results in pregnancy failure, but the precise function of folds remains unknown. Here, we uncover dynamic changes in the 3D uterine folding pattern during early pregnancy with the entire lumen forming pre-implantation transverse folds along the mesometrial-antimesometrial axis. Using a time course, we show that transverse folds are formed before embryo spacing, whereas implantation chambers form as the embryo begins attachment. Thus, folds and chambers are two distinct structures. Transverse folds resolve to form a flat implantation region, after which an embryo arrives at its center to attach and form the post-implantation chamber. Our data also suggest that the implantation chamber facilitates embryo rotation and its alignment along the uterine mesometrial-antimesometrial axis. Using WNT5A- and RBPJ-deficient mice that display aberrant folds, we show that embryos trapped in longitudinal folds display misalignment of the embryo-uterine axes, abnormal chamber formation and defective post-implantation morphogenesis. These mouse models with disrupted uterine folding provide an opportunity to understand uterine structure-based mechanisms that are crucial for implantation and pregnancy success. This article has an associated 'The people behind the papers' interview.