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10 March 2022 Podocalyxin molecular characteristics and endometrial expression: high conservation between humans and macaques but divergence in mice
Bothidah Thach, Nirukshi Samarajeewa, Ying Li, Sophea Heng, Tesha Tsai, Mulyoto Pangestu, Sally Catt, Guiying Nie
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Abstract

Podocalyxin (PODXL) is a newly identified key negative regulator of human endometrial receptivity, specifically down-regulated in the luminal epithelium at receptivity to permit embryo implantation. Here, we bioinformatically compared the molecular characteristics of PODXL among the human, rhesus macaque, and mouse, determined by immunohistochemistry and in situ hybridization (mouse tissues) whether endometrial PODXL expression is conserved across the three species and examined if PODXL inhibits mouse embryo attachment in vitro. The PODXL gene, mRNA, and protein sequences showed greater similarities between humans and macaques than with mice. In all species, PODXL was expressed in endometrial luminal/glandular epithelia and endothelia. In macaques (n = 9), luminal PODXL was significantly down-regulated when receptivity is developed, consistent with the pattern found in women. At receptivity, PODXL was also reduced in shallow glands, whereas endothelial expression was unchanged across the menstrual cycle. In mice, endometrial PODXL did not vary considerably across the estrous cycle (n = 16); however, around embryo attachment on d4.5 of pregnancy (n = 4), luminal PODXL was greatly reduced especially near the site of embryo attachment. Mouse embryos failed to attach or thrive when co-cultured on a monolayer of Ishikawa cells overexpressing PODXL. Thus, endometrial luminal PODXL expression is down-regulated for embryo implantation in all species examined, and PODXL inhibits mouse embryo implantation. Rhesus macaques share greater conservations with humans than mice in PODXL molecular characteristics and regulation, thus represent a better animal model for functional studies of endometrial PODXL for treatment of human fertility.

Summary Sentence

Podocalyxin, a key negative regulator of human endometrial receptivity, is also down-regulated in the luminal epithelium in both the rhesus macaque and mouse uterus for embryo implantation, and podocalyxin inhibits mouse embryo attachment in vitro.

© The Author(s) 2022. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
Bothidah Thach, Nirukshi Samarajeewa, Ying Li, Sophea Heng, Tesha Tsai, Mulyoto Pangestu, Sally Catt, and Guiying Nie "Podocalyxin molecular characteristics and endometrial expression: high conservation between humans and macaques but divergence in mice," Biology of Reproduction 106(6), 1143-1158, (10 March 2022). https://doi.org/10.1093/biolre/ioac053
Received: 3 October 2021; Accepted: 3 March 2022; Published: 10 March 2022
JOURNAL ARTICLE
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KEYWORDS
embryo implantation
endometrial receptivity
fertility
Mouse
podocalyxin
Rhesus macaque
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