STK3/4 Expression Is Regulated in Uterine Endometrial Cells during the Estrous Cycle

Abstract

The uterus is dynamically regulated in response to various signaling triggered by hormones during the estrous cycle. The Hippo signaling pathway is known as an important signaling for regulating cellular processes during development by balancing between cell growth and apoptosis. Serine/threonine protein kinase 3/4 (STK3/4) is a key component of the Hippo signaling network. However, the regulation of STK3/4-Hippo signaling in the uterus is little known. In this study, we investigated the regulation and expression of STK3/4 in the uterine endometrium during the estrous cycle. STK3/4 expression was dynamically regulated in the uterus during the estrous cycle. STK3/4 protein expression was gradually increased from the diestrus stage and reached the highest in the estrus stage. STK3/4 was exclusively localized in the luminal and glandular epithelial cells of the uterus, and phosphorylated STK3/4 was also increased at the estrus stage. Moreover, the increase of STK3/4 expression in uteri was induced by administration of estradiol, but not by progesterone injection in ovariectomized mice. Pretreatment with an estrogen receptor antagonist ICI 182,780 reduced estrogen-induced STK3/4 expression and its phosphorylation. The estrogen-induced STK3/4 expression was related to the increase in phosphorylation of downstream targets including LATS1/2 and YAP. These findings suggest that STK3/4-Hippo signaling acts a novel signaling pathway in the uterine epithelium and STK3/4-Hippo is one of key molecules for connecting between the estrogen downstream signaling pathway and the Hippo signaling pathway leading to regulate dynamic uterine epithelium during the estrous cycle.

Identification of a Goat Intersexuality-Associated Novel Variant Through Genome-Wide Resequencing and Hi-C

“…Within the top 1% selection window, a series of genes were identified and found to be deeply involved in animal reproduction and multiple developmental processes. For example, STK3 is a key molecule that connects the downstream signaling pathway of estrogen and the Hippo signaling pathway; it also regulates the dynamic development of the uterine epithelium during the estrous cycle through the signal transduction of uterine epithelial cells (Moon et al, 2019 ). STK3 was annotated to other signaling pathways, such as the MAPK (Bogani et al, 2009 ; Warr et al, 2016 ) and Hippo signaling pathways, that also play an important role in gonadal development and sex determination (Frum et al, 2018 ; Devos et al, 2020 ).…”

Hippo Signaling in the Endometrium

“…The regulation of STK3/4 and its downstream targets is mediated by p38-MAPK, an estrogen receptor-dependent intracellular signaling pathway. Our previous study showed that the phosphorylation of LATS1/2 was faster than that of STK3/4, which may occur through an unknown signaling pathway for the phosphorylation of LATS1/2 in uterine dynamics during the estrous cycle [ 71 ].…”

Narrow-Headed Voles Species Complex (Cricetidae, Rodentia): Evidence for Species Differentiation Inferred from Transcriptome Data

“…The list of genes with contrasting SNPs associated with different reproductive processes included CITED1 (participates in the development of the placenta, as well as in the growth and survival of embryos [99]), CNOT6L (involved in the meiotic cell cycle in mouse oocytes [100]), FNBP1L (associated with male fertility [101]), HERC2 (mutations in this gene lead to sperm acrosome defects, other developmental abnormalities, and juvenile lethality of mice [102]), KMT2D (expressing in male germ cells and regulating spermatogonial differentiation [103]), NFIX (involved in the formation of the synaptonemal complex during male meiosis [104]), PTK7 (involved in the sexually dimorphic development of the genital tract [105]), STK3 (involved in the regulation of dynamic uterine epithelium during the estrous cycle [106]), and TAF9B (involved in mice embryonic germ cell development [107]).…”