Targeted depletion of uterine glandular Foxa2 induces embryonic diapause in mice

Matsuo, Mitsuyoshi; Yuan, Jia; Kim, Yeon Sun; Dewar, Amanda; Fujita, Hidetoshi; Dey, Sudhansu K.; Sun, Xiaofei

doi:10.7554/elife.78277

Cited by 11 publications

(12 citation statements)

References 37 publications

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“…The gland bud phenotype is remarkably similar to gland structure observed in uteri with neonatal deletion of Foxa2 ( Fig. 4F in reference (49)). Depletion of ESR1 in the adult epithelium does not cause any quantifiable structural gland phenotypes, suggesting that epithelial ESR1 signaling during puberty is required for gland branching.…”

Section: Discussionsupporting

confidence: 75%

Murine uterine gland branching is necessary for gland function in implantation

Granger,

Fitch,

Shen

et al. 2023

Preprint

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Uterine glands are branched, tubular structures whose secretions are essential for pregnancy success. It is known that pre-implantation glandular expression of leukemia inhibitory factor (LIF) is crucial for embryo implantation, however contribution of uterine gland structure to gland secretions such as LIF is not known. Here we use mice deficient in estrogen receptor 1 (ESR1) signaling to uncover the role of ESR1 signaling in gland branching and the role of a branched structure in LIF secretion and embryo implantation. We observed that deletion of ESR1 in neonatal uterine epithelium, stroma and muscle using the progesterone receptorPgrCrecauses a block in uterine gland development at the gland bud stage. Embryonic epithelial deletion of ESR1 using a mullerian duct Cre line -Pax2Cre, displays gland bud elongation but a failure in gland branching. Surprisingly, adult uterine epithelial deletion of ESR1 using the lactoferrin-Cre (LtfCre) displays normally branched uterine glands. Intriguingly, unbranched glands fromPax2CreEsr1flox/floxuteri fail to express glandular pre-implantationLif,preventing implantation chamber formation and embryo alignment along the uterine mesometrial-antimesometrial axis. In contrast, branched glands fromLtfCreEsr1flox/floxuteri display reduced expression of glandularLifresulting in delayed implantation chamber formation and embryo-uterine axes alignment but deliver a normal number of pups. Finally, pre-pubertal unbranched glands in control mice expressLifin the luminal epithelium but fail to expressLifin the glandular epithelium even in the presence of estrogen. These data strongly suggest that branched glands are necessary for pre-implantation glandularLifexpression for implantation success. Our study is the first to identify a relationship between the branched structure and secretory function of uterine glands and provides a framework for understanding how uterine gland structure-function contributes to pregnancy success.

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Section: Discussionsupporting

confidence: 75%

Murine uterine gland branching is necessary for gland function in implantation

Granger,

Fitch,

Shen

et al. 2023

Preprint

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“…In that study, the authors have shown that dormant blastocysts are recovered from these mice on day 8 of pregnancy with persistent expression of uterine MSX1, a gene critical to maintaining the uterine quiescent state [17]. Interestingly, progesterone and anti-estrogen can prolong uterine quiescence [17].…”

Section: Discussionmentioning

confidence: 93%

“…A very recent study on the role of MSX1 in reproduction was carried out on mice embryonic diapause [17]. Embryonic diapause in mice is a reproductive strategy in which embryo development and growth are temporarily halted in utero to ensure neonatal and maternal survival in adverse external conditions [17]. In that study, the authors have shown that dormant blastocysts are recovered from these mice on day 8 of pregnancy with persistent expression of uterine MSX1, a gene critical to maintaining the uterine quiescent state [17].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, another animal based study found that progesterone inhibits uterine gland development in the neonatal mouse uterus and downregulated MSX1 [16]. A very recent study on the role of MSX1 in reproduction was carried out on mice embryonic diapause [17]. Embryonic diapause in mice is a reproductive strategy in which embryo development and growth are temporarily halted in utero to ensure neonatal and maternal survival in adverse external conditions [17].…”

Section: Discussionmentioning

confidence: 99%

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MSX1-expression during the different phases in healthy human endometrium

Eppich¹,

Kühn²,

Schmoeckel³

et al. 2023

Preprint

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Purpose: The human endometrium consists of different layers (basalis and functionalis) and undergoes different phases throughout the menstrual cycle. In a former paper our research group was able to describe MSX1 as a positive prognosticator in endometrial carcinomas. The aim of this study was to examine the MSX1 expression in healthy endometrial tissue throughout the different phases to gain more insight on the mechanics of MSX-regulation in the female reproductive system. Materials and Methods: In this retrospective study we investigated a total of 19 normal endometrial tissues (7 during proliferative phase and each 6 during early and late secretory phase). We used immunohistochemical staining and an immunoreactive score (IRS) to evaluate MSX1 expression. We also investigated correlations with other proteins, that have already been examined in our research group using the same patient collective. Results: MSX1 is highly expressed during the proliferative phase and downregulated at early and late secretory phase (p=0.018). Also, a positive correlation between MSX1 and the progesterone-receptor A (PR-A) (correlation coefficient (cc)=0.0671; p=0.024), the progesterone receptor B (PR-B) (cc=0.0691; p=0.018) was found. A trend towards negative correlation was recognized between MSX1 and Inhibin Beta-C-expression in glandular cells (cc=-0.583; p-value=0.060). Conclusion: MSX1 is known as a member of the muscle segment homeobox gene family. MSX1 is a p53-interacting protein and overexpression of homeobox MSX1 induced apoptosis of cancer cells. Here we show that MSX1 is highly expressed especially in the proliferative phase of glandular epithelial tissue of the normal endometrium. Because MSX1 is known to be downregulated by progesterone, the found correlation of MSX1 and both PR-A and -B may represent a direct regulation of the MSX1 gene by a PR-response element.

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“…Forkhead box A2 (FOXA2), a member of the FOXA family, belongs to a class of transcription factors with a winged helix structure in the DNA-binding region, which performs essential roles in embryonic growth and development, cell proliferation and differentiation, glucose metabolism, airway mucus homeostasis, and lipid metabolism by binding to specific DNA sequences and activating or repressing the transcriptional activity of target genes. [11][12][13][14] The relationship between FOXA2 and tumorigenesis and tumor development has been intensively studied in recent years. Studies have documented decreased FOXA2 expression in malignant tumors, such as liver and lung tumors, which contributes to tumor proliferation, migration, and invasion.…”

Section: Introductionmentioning

confidence: 99%

FOXA2 suppresses gallbladder carcinoma cell migration, invasion, and epithelial‐mesenchymal transition by targeting SERPINB5

Hong,

Chen,

Huang

et al. 2023

Environmental Toxicology

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BackgroundGallbladder cancer (GBC), a highly malignant gastrointestinal tumor, lacks effective therapies. Foxhead box A2 (FOXA2) is a tumor suppressor that is poorly expressed in various human malignancies. This study aimed to ascertain FOXA2 expression in GBC and its relevance to tumor metastasis, and to elucidate its regulatory mechanism with epithelial‐mesenchymal transition (EMT) as an entry point, in the hope of providing a potential therapeutic target for GBC.MethodsFOXA2 expression in GBC tissues was first detected using immunohistochemistry (IHC), followed by correlation analysis with clinicopathological characteristics and survival prognosis. Subsequently, the effects of FOXA2 on GBC cell migration and invasion, as well as EMT induction, were evaluated by scratch, Transwell, RT‐PCR, and Western blot assays, together with animal experimentation. Ultimately, mRNA sequencing was carried out to identify the key downstream target genes of FOXA2 in controlling the EMT process in GBC cells, and dual‐luciferase reporter and chromatin immunoprecipitation assays were used to determine its regulatory mechanism.ResultsFOXA2 was underexpressed in GBC tissues and inversely correlated with tumor node metastasis stage, lymph node metastasis, and poor patient prognosis. FOXA2 exerts suppressive effects on EMT and metastasis of GBC in vivo and in vitro. FOXA2 can impede GBC cell migratory and invasive functions and EMT by positively mediating serine protein kinase inhibitor B5 (SERPINB5) expression.ConclusionFOXA2 directly binds to the SERPINB5 promoter region to stimulate its transcription, thereby modulating the migration and invasion behaviors of GBC cells as well as the EMT process, which might be an effective therapeutic target against GBC.

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Targeted depletion of uterine glandular Foxa2 induces embryonic diapause in mice

Cited by 11 publications

References 37 publications

Murine uterine gland branching is necessary for gland function in implantation

Murine uterine gland branching is necessary for gland function in implantation

MSX1-expression during the different phases in healthy human endometrium

FOXA2 suppresses gallbladder carcinoma cell migration, invasion, and epithelial‐mesenchymal transition by targeting SERPINB5

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