Loss of APC function in mesenchymal cells surrounding the Müllerian duct leads to myometrial defects in adult mice

Wang, Yong-Yi; Jia, Yundan; Franken, Patrick; Smits, Ron; Ewing, Patricia C.; Lydon, John P.; DeMayo, Francesco J.; Burger, Curt W.; Grootegoed, J. Anton; Fodde, Riccardo; Blok, Leen J.

doi:10.1016/j.mce.2011.05.026

Cited by 13 publications

(6 citation statements)

References 32 publications

(38 reference statements)

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“…Two Cre transgenic lines, Amhr2 cre/+ (Amhr2-Cre) and PR cre/+ (PR-Cre), have been mainly utilized to delete genes of interest in female reproductive tracts 9 10 11 12 . Amhr2-Cre is expressed embryonically in the mesenchyme of the developing Mullerian ducts, and postnatally in ovarian granulosa cells and the stromal and myometrial layers of female reproductive tracts 25 26 27 . As expected from Amhr2 expression profiles, Dicer flox/flox ;Amhr2 cre/+ mice are infertile due to multiple defects in female reproductive tracts such as disorganized oviducts with cysts and shorter uterine horns, although these mice have normal mating behavior 9 10 11 that is not shown in Dgcr8 d/d mice ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Deficiency in DGCR8-dependent canonical microRNAs causes infertility due to multiple abnormalities during uterine development in mice

Kim

et al. 2016

Sci Rep

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DGCR8 is an RNA-binding protein that interacts with DROSHA to produce pre-microRNA in the nucleus, while DICER generates not only mature microRNA, but also endogenous small interfering RNAs in the cytoplasm. Here, we produced Dgcr8 conditional knock-out mice using progesterone receptor (PR)-Cre (Dgcr8d/d) and demonstrated that canonical microRNAs dependent on the DROSHA-DGCR8 complex are required for uterine development as well as female fertility in mice. Adult Dgcr8d/d females neither underwent regular reproductive cycles nor produced pups, whereas administration of exogenous gonadotropins induced normal ovulation in these mice. Interestingly, immune cells associated with acute inflammation aberrantly infiltrated into reproductive organs of pregnant Dgcr8d/d mice. Regarding uterine development, multiple uterine abnormalities were noticeable at 4 weeks of age when PR is significantly increased, and the severity of these deformities increased over time. Gland formation and myometrial layers were significantly reduced, and the stromal cell compartment did not expand and became atrophic during uterine development in these mice. These results were consistent with aberrantly reduced stromal cell proliferation and completely failed decidualization. Collectively, we suggest that DGCR8-dependent canonical microRNAs are essential for uterine development and physiological processes such as proper immune modulation, reproductive cycle, and steroid hormone responsiveness in mice.

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Section: Discussionmentioning

confidence: 99%

Deficiency in DGCR8-dependent canonical microRNAs causes infertility due to multiple abnormalities during uterine development in mice

Kim

et al. 2016

Sci Rep

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“…The disruption of uterine smooth muscle structure in the Tgfbr1 cKO mice could potentially impede the contractility of the uterus or cause uterine rupture, with an adverse impact on pregnancy outcome. Emerging evidence suggests the involvement of the Wnt pathway in the maintenance of myometrium organization and integrity [79], [80]. Further investigations on the potential link between TGFBR1–mediated signaling and the Wnt pathway as well as the direct impact of the myometrial abnormalities resulting from loss of TGFβ/Wnt signaling components on reproductive potential may shed mechanistic light on reproductive disorders associated with smooth muscle pathology.…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor β Receptor Type 1 Is Essential for Female Reproductive Tract Integrity and Function

et al. 2011

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The transforming growth factor β (TGFβ) superfamily proteins are principle regulators of numerous biological functions. Although recent studies have gained tremendous insights into this growth factor family in female reproduction, the functions of the receptors in vivo remain poorly defined. TGFβ type 1 receptor (TGFBR1), also known as activin receptor-like kinase 5, is the major type 1 receptor for TGFβ ligands. Tgfbr1 null mice die embryonically, precluding functional characterization of TGFBR1 postnatally. To study TGFBR1–mediated signaling in female reproduction, we generated a mouse model with conditional knockout (cKO) of Tgfbr1 in the female reproductive tract using anti-Müllerian hormone receptor type 2 promoter-driven Cre recombinase. We found that Tgfbr1 cKO females are sterile. However, unlike its role in growth differentiation factor 9 (GDF9) signaling in vitro, TGFBR1 seems to be dispensable for GDF9 signaling in vivo. Strikingly, we discovered that the Tgfbr1 cKO females develop oviductal diverticula, which impair embryo development and transit of embryos to the uterus. Molecular analysis further demonstrated the dysregulation of several cell differentiation and migration genes (e.g., Krt12, Ace2, and MyoR) that are potentially associated with female reproductive tract development. Moreover, defective smooth muscle development was also revealed in the uteri of the Tgfbr1 cKO mice. Thus, TGFBR1 is required for female reproductive tract integrity and function, and disruption of TGFBR1–mediated signaling leads to catastrophic structural and functional consequences in the oviduct and uterus.

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“…Furthermore, because SRC family members have been detected in one or more uterine cell types [120], the selective functions of epithelial, stromal, and/or myometrial SRCs to a particular normal or abnormal uterine response will be critical to further resolving the functional role of each uterine SRC at the cellular level. With the availability of cell type-specific cre/loxP strategies [127][128][129][130][131], this type of research is now achievable.…”

Section: Perspectivesmentioning

confidence: 99%

The p160/Steroid Receptor Coactivator Family: Potent Arbiters of Uterine Physiology and Dysfunction1

Szwarc

Kommagani

Lessey

et al. 2014

Biology of Reproduction

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The p160/steroid receptor coactivator (SRC) family comprises three pleiotropic coregulators (SRC-1, SRC-2, and SRC-3; otherwise known as NCOA1, NCOA2, and NCOA3, respectively), which modulate a wide spectrum of physiological responses and clinicopathologies. Such pleiotropy is achieved through their inherent structural complexity, which allows this coregulator class to control both nuclear receptor and non-nuclear receptor signaling. As observed in other physiologic systems, members of the SRC family have recently been shown to play pivotal roles in uterine biology and pathobiology. In the murine uterus, SRC-1 is required to launch a full steroid hormone response, without which endometrial decidualization is markedly attenuated. From "dovetailing" clinical and mouse studies, an isoform of SRC-1 was recently identified which promotes endometriosis by reprogramming endometrial cells to evade apoptosis and to colonize as endometriotic lesions within the peritoneal cavity. The endometrium fails to decidualize without SRC-2, which accounts for the infertility phenotype exhibited by mice devoid of this coregulator. In related studies on human endometrial stromal cells, SRC-2 was shown to act as a molecular "pacemaker" of the glycolytic flux. This finding is significant because acceleration of the glycolytic flux provides the necessary bioenergy and biomolecules for endometrial stromal cells to switch from quiescence to a proliferative phenotype, a critical underpinning in the decidual progression program. Although studies on uterine SRC-3 function are in their early stages, clinical studies provide tantalizing support for the proposal that SRC-3 is causally linked to endometrial hyperplasia as well as with endometrial pathologies in patients diagnosed with polycystic ovary syndrome. This proposal is now driving the development and application of innovative technologies, particularly in the mouse, to further understand the functional role of this elusive uterine coregulator in normal and abnormal physiologic contexts. Because dysregulation of this coregulator triad potentially presents a triple threat for increased risk of subfecundity, infertility, or endometrial disease, a clearer understanding of the individual and combinatorial roles of these coregulators in uterine function is urgently required. This minireview summarizes our current understanding of uterine SRC function, with a particular emphasis on the next critical questions that need to be addressed to ensure significant expansion of our knowledge of this underexplored field of uterine biology.

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Loss of APC function in mesenchymal cells surrounding the Müllerian duct leads to myometrial defects in adult mice

Cited by 13 publications

References 32 publications

Deficiency in DGCR8-dependent canonical microRNAs causes infertility due to multiple abnormalities during uterine development in mice

Deficiency in DGCR8-dependent canonical microRNAs causes infertility due to multiple abnormalities during uterine development in mice

Transforming Growth Factor β Receptor Type 1 Is Essential for Female Reproductive Tract Integrity and Function

The p160/Steroid Receptor Coactivator Family: Potent Arbiters of Uterine Physiology and Dysfunction1

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