Serum Progesterone Levels in the Pregnant and Postpartum Laboratory Mouse

Virgo, Bruce B.; Bellward, Gail D.

doi:10.1210/endo-95-5-1486

Cited by 124 publications

(84 citation statements)

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“…Consequently, after 17.5 dpc, when P 4 levels and PR function decline (27), ZEB1 mRNA and protein in the pregnant mouse uterus are significantly reduced. Because ZEB1 directly binds and represses the miR-200b/429 promoter (17,18) (Fig.…”

Section: Discussionmentioning

confidence: 99%

miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor

Renthal

Chen²,

Williams

et al. 2010

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

258

239

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Throughout most of pregnancy, uterine quiescence is maintained by increased progesterone receptor (PR) transcriptional activity, whereas spontaneous labor is initiated/facilitated by a concerted series of biochemical events that activate inflammatory pathways and have a negative impact on PR function. In this study, we uncovered a previously undescribed regulatory pathway whereby micro-RNAs (miRNAs) serve as hormonally modulated and conserved mediators of contraction-associated genes in the pregnant uterus in the mouse and human. Using miRNA and gene expression microarray analyses of uterine tissues, we identified a conserved family of miRNAs, the miR-200 family, that is highly induced at term in both mice and humans as well as two coordinately downregulated targets, zinc finger E-box binding homeobox proteins ZEB1 and ZEB2, which act as transcriptional repressors. We also observed up-regulation of the miR-200 family and down-regulation of ZEB1 and ZEB2 in two different mouse models of preterm labor. We further demonstrated that ZEB1 is directly up-regulated by the action of progesterone (P 4 )/PR at the ZEB1 promoter. Excitingly, we observed that ZEB1 and ZEB2 inhibit expression of the contractionassociated genes, oxytocin receptor and connexin-43, and block oxytocin-induced contractility in human myometrial cells. Together, these findings implicate the miR-200 family and their targets, ZEB1 and ZEB2, as unique P 4 /PR-mediated regulators of uterine quiescence and contractility during pregnancy and labor and shed light on the molecular mechanisms involved in preterm birth.A lthough premature labor is the leading cause of neonatal morbidity and mortality in developed countries, the signaling mechanisms that maintain uterine quiescence during pregnancy and promote increased uterine contractility leading to labor at term and preterm remain incompletely defined (1). In mammalian pregnancy, uterine quiescence is maintained by elevated circulating progesterone (P 4 ) acting via the progesterone receptor (PR). Conversely, parturition is associated with a decline in maternal circulating P 4 and/or a decrease in the function of the PR, termed "functional P 4 withdrawal," (2, 3) and an increased inflammatory response within the uterus and cervix (4). Studies from a number of laboratories, including our own, suggest that P 4 and PR maintain uterine quiescence until term by inhibiting expression of contraction-associated genes [e.g., connexin-43 (CXN-43), oxytocin receptor (OXTR), cyclooxygenase 2 (COX-2)] in the myometrium, in part, via anti-inflammatory actions. For example, P 4 and PR inhibit activation of COX-2 expression in myometrial cells through direct interaction of PR with NF-κB p65 (5) and by P 4 -induced expression of the NF-κB inhibitor, IκB-α (6).Recently, it has been shown that micro-RNAs (miRNAs) play especially powerful roles in vascular smooth muscle cells and in female reproduction, wherein they have been implicated in proliferation, differentiation, and hormone responsiveness (7-9). The identification o...

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Section: Discussionmentioning

confidence: 99%

miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor

Renthal

Chen²,

Williams

et al. 2010

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

258

239

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“…In the mouse, loss of P 4 function at term is achieved by a decline in ovarian P 4 synthesis (Virgo & Bellward 1974), increased local metabolism of P 4 (Mahendroo et al 1996, Ishida et al 2007, and a change in expression of P 4 receptor isoforms and coactivators (Fang et al 2002, Condon et al 2003. In the human, circulating levels of P 4 do not decline before birth due to its synthesis in the placenta.…”

Section: Relevance To Cervical Remodeling In Womenmentioning

confidence: 99%

Cervical remodeling in term and preterm birth: insights from an animal model

Mahendroo¹

2012

Reproduction

176

148

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Proper cervical function is essential for a normal pregnancy and birth to occur. Understanding the mechanisms that take place in normal pregnancy will allow a better comprehension of the complications involved in premature cervical remodeling and lead to better methods of diagnostics and prevention for preterm birth. Unfortunately, human samples are not easily available, and samples that are collected are often confounded by variations in timing and region of cervix from which sample is collected. Animal models, specifically the mouse, have facilitated a great deal of exploration into the mechanisms of cervical function and pathways of preterm birth. This review highlights some of the groundbreaking discoveries that have arisen from murine research including 1) the identification of early pregnancy changes in collagen fibril processing and assembly that result in progressive modifications to collagen architecture with subsequent loss of tissue stiffness during pregnancy, 2) the determination that immune cells are not key to cervical ripening at term but have diverse phenotypes and functions in postpartum repair, and 3) the finding that the process of preterm cervical ripening can differ from term ripening and is dependent on the etiology of prematurity. These findings, which are relevant to human cervical biology, provide new insights that will allow targeted studies on the human cervix as well as identify potential biomarkers for early detection of premature cervical ripening and development of improved therapies to prevent premature ripening of the cervix and subsequent preterm birth.

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“…It has been shown in cycling mice by in situ hybridization that the PRL-R mRNA is found in the epithelial cells of mammary ducts and alveoli [5], but PRL-R numbers begin to decrease in early pregnancy and are maintained at a low level until late pregnancy [3,4] The levels of circulating progesterone begin to rise during early pregnancy and are maintained at a high level until the end of pregnancy in mice [6][7][8]. The withdrawal of circulating progesterone causes an increase in the number of mammary PRLRs in pregnant mice and rats [9,10].…”

Section: Growthmentioning

confidence: 99%

The Regulation of the Prolactin Receptor Gene Expression in the Mammary Gland of Early Pregnant Mouse.

et al. 1997

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Abstract. The purpose of this research was to examine the hormonal regulation of the PRL receptor (PRL-R) gene expression in the mammary gland of early pregnant mouse. Following reversetranscription, the quantity of PRL-R mRNA was determined by the competitive polymerase chain reaction. The level of long form PRL-R (PRL-RL) mRNA changed cyclically with the highest at estrus and the lowest at diestrus II. PRL-RL mRNA was maintained at high levels for the first 3 days of pregnancy but declined to lower levels on day 5. Mice ovariectomized on day 2 of pregnancy maintained the same level of PRL-RL mRNA during the 24 h-period.The level of PRL-R mRNA increased more than 2-and 2.7-fold with 17f3-estradiol and PRL, respectively, and the progesterone concentration decreased its levels to 71% of the vehicle-injected control. The increasing action with 17/3-estradiol and PRL was suppressed by administration of progesterone.Mice ovariectomized on day 3 had a 1.8-fold higher level than that of the sham-operated control. The short form of PRL-R remained at low levels throughout the experiments. The results suggested that the expression of the PRL-R gene was suppressed when serum progesterone increased during early pregnancy.

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Serum Progesterone Levels in the Pregnant and Postpartum Laboratory Mouse

Cited by 124 publications

References 1 publication

miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor

miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor

Cervical remodeling in term and preterm birth: insights from an animal model

The Regulation of the Prolactin Receptor Gene Expression in the Mammary Gland of Early Pregnant Mouse.

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