WNK1 regulates uterine homeostasis and its ability to support pregnancy.

Ru-Pin Alicia Chi,Chou-Long Huang,Tianyuan Wang,John P Lydon,San-Pin Wu,Francesco J Demayo,Steven L Young

doi:10.1172/jci.insight.141832

Abstract

WNK1 (with no lysine [K] kinase 1) is an atypical kinase protein ubiquitously expressed in humans and mice. A mutation in its encoding gene causes hypertension in humans, which is associated with abnormal ion homeostasis. WNK1 is critical for in vitro decidualization in human endometrial stromal cells, thereby demonstrating its importance in female reproduction. Using a mouse model, WNK1 was ablated in the female reproductive tract to define its in vivo role in uterine biology. Loss of WNK1 altered uterine morphology, causing endometrial epithelial hyperplasia, adenomyotic features, and a delay in embryo implantation, ultimately resulting in compromised fertility. Combining transcriptomic, proteomic, and interactomic analyses revealed a potentially novel regulatory pathway whereby WNK1 represses AKT phosphorylation through protein phosphatase 2A (PP2A) in endometrial cells from both humans and mice. We show that WNK1 interacted with PPP2R1A, the alpha isoform of the PP2A scaffold subunit. This maintained the levels of PP2A subunits and stabilized its activity, which then dephosphorylated AKT. Therefore, loss of WNK1 reduced PP2A activity, causing AKT hypersignaling. Using FOXO1 as a readout of AKT activity, we demonstrate that there was escalated FOXO1 phosphorylation and nuclear exclusion, leading to a disruption in the expression of genes that are crucial for embryo implantation.

Highlights

Aberrant embryo implantation results in a ripple effect leading to pregnancy complications and miscarriages [1]
We explored this further by examining the in vivo function of WNK1, and we demonstrate here that loss of WNK1 led to hyperplasia, adenomyosis-like features, and impaired implantation
We show for the first time to our knowledge that WNK1 robustly repressed AKT activity and that loss of WNK1 led to increased AKT phosphorylation and signaling

Summary

Introduction

Aberrant embryo implantation results in a ripple effect leading to pregnancy complications and miscarriages [1]. WNK1 (with no lysine [K] kinase 1) has been identified as a potential regulator of uterine function acting downstream of EGFR that regulates endometrial stroma cell proliferation, migration, and differentiation in vitro [2, 3]. These findings indicate a previously unrecognized function of WNK1 in the female reproductive tract and led us to hypothesize that WNK1 is a mediator of uterine function. WNK1’s regulatory function on OSR1 is critical for cardiovascular development, thereby contributing to embryonic lethality when ablated from the endothelium [14, 15] These findings suggest that WNK1 exhibits organ-specific physiological functions, the underlying cellular components regulated by WNK1 may share similarity between the different tissues

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Results

Conclusion