Attenuated retinoic acid signaling is among the early responses in mouse uterus approaching embryo attachment

Honglu Diao; Shuo Xiao; Tong Zhou; Taylor E Martin; Wendy T Watford; Xiaoqin Ye

doi:10.1097/RD9.0000000000000090

Attenuated retinoic acid signaling is among the early responses in mouse uterus approaching embryo attachment

Reprod Dev Med. 2024 Mar;8(1):61-65. doi: 10.1097/RD9.0000000000000090. Epub 2024 Jan 15.

Authors

Honglu Diao¹, Shuo Xiao^{1

2}, Tong Zhou³, Taylor E Martin^{1

2}, Wendy T Watford⁴, Xiaoqin Ye^{1

2}

Affiliations

¹ Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA.
² Interdisciplinary Toxicology Program, University of Georgia, Athens, GA 30602, USA.
³ Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA.
⁴ Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA.

Abstract

The uterus is transiently receptive for embryo implantation. It remains to be understood why the uterus does not reject a semi-allogeneic embryo (to the biological mother) or an allogeneic embryo (to a surrogate) for implantation. To gain insights, we examined uterine early response genes approaching embryo attachment on day 3 post coitum (D3) at 22 hours when blue dye reaction, an indication of embryo attachment, had not manifested in mice. C57BL/6 pseudo-pregnant (control) and pregnant mouse uteri were collected on D3 at 22 hours for microarray analysis. The self-assembling-manifold (SAM) algorithm identified 21,858 unique probesets. Principal component analysis indicated a clear separation between the pseudo-pregnant and pregnant groups. There were 106 upregulated and five downregulated protein-coding genes in the pregnant uterus with fold change (fc) >1.5 and q value <5%. Gene ontology (GO) analysis of the 106 upregulated genes revealed 38 significant GO biological process (GOBP) terms (P <0.05), and 32 (84%) of them were associated with immune responses, with a dominant natural killer (NK) cell activation signature. Among the top eight upregulated protein-coding genes, Cyp26a1 inactivates retinoic acid (RA) while Lrat promotes vitamin A storage, both of which are expected to attenuate RA bioavailability; Atp6v0d2 and Gjb2 play roles in ion transport and transmembrane transport; Gzmb, Gzmc, and Il2rb are involved in immune responses; and Tdo2 is important for kynurenine pathway. Most of these genes or their related pathways have functions in immune regulations. RA signaling has been implicated in immune tolerance and immune homeostasis, and uterine NK cells have been implicated in immunotolerance at the maternal-fetal interface in the placenta. The mechanisms of immune responses approaching embryo attachment remain to be elucidated. The coordinated effects of the early response genes may hold the keys to the question of why the uterus does not reject an implanting embryo.

Keywords: Embryo attachment; Natural killer cell activation signature; Pregnant uterus; Pseudo-pregnant uterus; Retinoic acid bioavailability; Transmembrane transport and ion transport.