Uterine glands impact uterine receptivity, luminal fluid homeostasis and blastocyst implantation

Kelleher, Andrew M.; Burns, Gregory W.; Behura, Susanta K.; Wu, Guoyao; Spencer, Thomas E.

doi:10.1038/srep38078

Cited by 73 publications

(72 citation statements)

References 81 publications

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“…injections of LIF into GD 3.5 FOXA2-deficient mice with or without uterine glands elicited blastocyst implantation but rescued pregnancy only in gland-containing Ltf iCre/+ Foxa2 f/f mice. Given that LIF could not be detected in the uterine luminal fluid of wild-type mice by either mass spectrometry or ELISA (38), LIF may be preferentially secreted in a basolateral manner from the glands and impact uterine receptivity for blastocyst implantation as well as stromal cell decidualization (38). Another key finding here is that FOXA2 is essential for adult uterine function and particularly for Lif expression by the uterine glands of mice on GD 3.5.…”

Section: On Gd 35 Induces the Expression Of Lif In The Glands Of Thementioning

confidence: 94%

“…Those uteri contained unimplanted blastocysts in which the trophectoderm was in clear apposition to an intact LE with no evidence of stromal cell decidualization. Similarly, mice lacking uterine glands do not express Lif and exhibit a defect in blastocyst implantation (12,(33)(34)(35)(36)(37)(38). Thus, uterine glands and, by inference, their secretions do not influence preimplantation embryo growth and development but are required for implantation and successful establishment and maintenance of pregnancy.…”

Section: Discussionmentioning

confidence: 99%

“…Of note, blastocysts from UGKO mice are implantation competent when transferred into normal uteri (38). Here, i.p.…”

Section: On Gd 35 Induces the Expression Of Lif In The Glands Of Thementioning

confidence: 99%

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Forkhead box a2 (FOXA2) is essential for uterine function and fertility

Kelleher

Wang

Pru

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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126

177

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Establishment of pregnancy is a critical event, and failure of embryo implantation and stromal decidualization in the uterus contribute to significant numbers of pregnancy losses in women. Glands of the uterus are essential for establishment of pregnancy in mice and likely in humans. Forkhead box a2 (FOXA2) is a transcription factor expressed specifically in the glands of the uterus and is a critical regulator of postnatal uterine gland differentiation in mice. In this study, we conditionally deleted FOXA2 in the adult mouse uterus using the lactotransferrin Cre (Ltf-Cre) model and in the neonatal mouse uterus using the progesterone receptor Cre (Pgr-Cre) model. The uteri of adult FOXA2-deleted mice were morphologically normal and contained glands, whereas the uteri of neonatal FOXA2-deleted mice were completely aglandular. Notably, adult FOXA2-deleted mice are completely infertile because of defects in blastocyst implantation and stromal cell decidualization. Leukemia inhibitory factor (LIF), a critical implantation factor of uterine gland origin, was not expressed during early pregnancy in adult FOXA2-deleted mice. Intriguingly, i.p. injections of LIF initiated blastocyst implantation in the uteri of both gland-containing and glandless adult FOXA2-deleted mice. Although pregnancy was rescued by LIF and was maintained to term in uterine gland-containing adult FOXA2-deleted mice, pregnancy failed by day 10 in neonatal FOXA2-deleted mice lacking uterine glands. These studies reveal a previously unrecognized role for FOXA2 in regulation of adult uterine function and fertility and provide original evidence that uterine glands and, by inference, their secretions play important roles in blastocyst implantation and stromal cell decidualization.T he uterus is comprised of two tissue compartments, the endometrium and the myometrium. The endometrium contains three cell types, luminal epithelium (LE), glandular epithelium (GE), and stroma. In mice, the uterus becomes receptive to blastocyst implantation on gestational day (GD) 4 (with the observation of a postcoital vaginal plug designated GD 0.5); it is prereceptive on GD 1-3, and by the afternoon of GD 5 it becomes nonreceptive (refractory) (1-3). Dynamic changes in ovarian estrogen and progesterone production act via the uterus to regulate uterine receptivity, blastocyst implantation, and stromal cell decidualization necessary for the establishment of pregnancy (4-6). The implantation process, which is initiated by the attachment of the blastocyst trophectoderm to the receptive LE, occurs before or right after midnight in the evening of GD 4 and becomes more prominent by the morning of GD 5. By GD 6, the trophectoderm begins to contact directly stromal cells that then begin to differentiate into decidual cells, which are required for successful pregnancy because they regulate placental development and local maternal immune responses (7,8).The infertility observed in leukemia inhibitory factor (Lif)-null mice and uterine gland-knockout (UGKO) mice and sheep established ...

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Section: On Gd 35 Induces the Expression Of Lif In The Glands Of Thementioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Forkhead box a2 (FOXA2) is essential for uterine function and fertility

Kelleher

Wang

Pru

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

126

177

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“…In humans and animals like; rodents and sheep, secretory products of the endometrial glands were necessary for peri-implantation conceptus survival and development in addition to establishment of uterine receptivity and blastocyst implantation [36,38,40,41]. Uterine glands secrete bioactive substances that regulate uterine luminal fluid (ULF) homeostasis and regulate uterine receptivity for blastocyst implantation.…”

Section: Discussionmentioning

confidence: 99%

“…The progesterone receptor regulates implantation, decidualization, and glandular development via a complex paracrine signaling network [35]. Progesterone and progesterone receptor (PR) regulate endometrial gland morphogenesis and terminal differentiated function to maintain pregnancy [23] by regulation of a number of known gland-specific genes [36].…”

Section: Discussionmentioning

confidence: 99%

Morphological, Histological and Immunohistochemical Study of the Rabbit Uterus during Pseudopregnancy

Abd-Elkareem¹

2017

J Cytol Histol

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Ten mature virgin rabbit does (4-5 months old) with mean weight of 2.4 kg were induced to ovulate; by intramuscular injection of HCG (50-70 IU). The day of induction was considered 0 days. Uteri were obtained from 14 h, 3, 7, 18 days post induction. At first stage of pseudopregnancy; the two uteri became hyperemic and slightly swollen. The uterine epithelium and endometrial glands epithelium were of columnar type with oval basal nuclei. The endometrial glands were few in number and small in size. The endometrial glands showed apocrine activity. The uterus had six longitudinal folds and the uterine epithelium form crypts. The endometrium had slight vascularization. At middle stage of pseudopregnancy, the two uteri became hyperemic and more swollen. This stage characterized by; mucosal folding, glandular formation, epithelial proliferation and thickening of the uterine wall. At last stage of pseudopregnancy; the two uteri became flaccid and more swollen. This stage characterized by dramatic changes in the uterine architecture in the form of: increased epithelial proliferation and crypt formation increase the complexity of luminal folding, increase in length, size and abundance of the uterine endometrial glands, increase in the uterine micro vascular development (increased abundance of the large microvessels and development of subepithelial capillary plexuses). Tunica vascularis could be demonstrated between the inner circular and outer longitudinal smooth muscle fibers of the myometrium at the all stages of psedopregnancy. Telocytes with its characteristic morphology could be demonstrated in the myometrium of the rabbit uterus during pseudopregnancy. Cell-specific immuno-localization of progesterone receptors alpha (PRA) in the rabbit uterus during pseudopregnancy revealed that, there were mild, moderate and strong nuclear PRA immunostaining in the endometrial epithelial cells, endometrial glands and in the smooth muscles fibers of the myometrium of the first, middle and last stages of pseudopregnancy respectively.The present study revealed that the morphological, histological and immunohistochemical changes in the rabbit uterus during pseudopregnancy resembled that occurred during early stage of pregnancy. These changes were characterized by dramatic changes in the uterine architecture in the form of: increased epithelial proliferation and crypt formation increase the complexity of luminal folding, increase in length, size and abundance of the uterine endometrial glands, increase in the uterine microvascular development. These uterine changes were accompanied with PRA immunolocalization in the uterine tissues.

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Prss29 Cre recombinase mice are useful to study adult uterine gland function

Kelleher

Allen

Davis

et al. 2022

Genesis

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All mammalian uteri contain glands in their endometrium that develop only or primarily after birth. In mice, those endometrial glands govern post implantation pregnancy establishment via regulation of blastocyst implantation, stromal cell decidualization, and placental development. Here, we describe a new uterine glandular epithelium (GE) specific Cre recombinase mouse line that is useful for the study of uterine gland function during pregnancy. Utilizing CRISPR-Cas9 genome editing, Cre recombinase was inserted into the endogenous serine protease 29 precursor (Prss29) gene. Both Prss29 mRNA and Cre recombinase activity was specific to the GE of the mouse uterus following implantation, but was absent from other areas of the female reproductive tract. Next, Prss29-Cre mice were crossed with floxed forkhead box A2 (Foxa2) mice to conditionally delete Foxa2 specifically in the endometrial glands.Foxa2 was absent in the glands of the post-implantation uterus, and Foxa2 deleted mice exhibited complete infertility after their first pregnancy. These results establish that Prss29-Cre mice are a valuable resource to elucidate and explore the functions of glands in the adult uterus.

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Uterine glands impact uterine receptivity, luminal fluid homeostasis and blastocyst implantation

Cited by 73 publications

References 81 publications

Forkhead box a2 (FOXA2) is essential for uterine function and fertility

Forkhead box a2 (FOXA2) is essential for uterine function and fertility

Morphological, Histological and Immunohistochemical Study of the Rabbit Uterus during Pseudopregnancy

Prss29 Cre recombinase mice are useful to study adult uterine gland function

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