Complex Regulation of Calcium-Binding Protein D9k (Calbindin-D9k) in the Mouse Uterus During Early Pregnancy and at the Site of Embryo Implantation1

Nie, Guiying; Li, Ying; Wang, Jian; Minoura, Hiroyuki; Findlay, Jock K.; Salamonsen, Lois A.

doi:10.1095/biolreprod62.1.27

Cited by 58 publications

(49 citation statements)

References 49 publications

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“…Among the target genes there are calbindins and the HoxA10 gene which are critical for implantation in mice and in humans respectively (Benson et al 1996, Taylor et al 1998, Nie et al 2000, Salamonsen et al 2002, Du et al 2005 and are known to be transcriptionally regulated by vitamin D in different cell types (Rots et al 1998, Nie et al 2000, Du et al 2005. We have herein identified osteopontin as another possible target gene regulated by vitamin D. Osteopontin is an acidic member of the small integrin-binding ligand N-linked glycoprotein family of extracellular matrix proteins/cytokines.…”

Section: Discussionmentioning

confidence: 71%

“…In the last years, interest in this specific topic has been greatly increased for two reasons: (i) the development of mice deficient in VDR or 1 -OHase has revealed that these animals show impaired ovarian folliculogenesis and uterine hypoplasia (Yoshizawa et al 1997, Kinuta et al 2000, Panda et al 2001 and (ii) vitamin D seems to influence the reproductive system not only at the ovarian level but also at the endometrial level. Indeed, some of the genes recently identified to be uniquely regulated at the site of embryo implantation, for instance calbindinD9k in the mouse and the homeobox (Hox) A10 gene in humans, are vitamin D-dependent proteins (Rots et al 1998, Nie et al 2000, Salamonsen et al 2002, Du et al 2005.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, some of the genes recently identified to be uniquely regulated at the site of embryo implantation, for instance calbindinD9k in the mouse and the homeobox (Hox) A10 gene in humans, are vitamin D-dependent proteins (Rots et al 1998, Nie et al 2000, Salamonsen et al 2002, Du et al 2005.…”

Section: Introductionmentioning

confidence: 99%

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Cycling and early pregnant endometrium as a site of regulated expression of the vitamin D system

Viganò

Lattuada

Mangioni

et al. 2006

Journal of Molecular Endocrinology

171

119

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In addition to its calciotropic function, the secosteroid 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), has potent anti-proliferative/immunomodulatory effects on various tissues. Consistently, the enzyme that catalyzes the synthesis of 1,25(OH) 2 D 3 , 1 -hydroxylase (1 -OHase) and the vitamin D receptor have a widespread tissue distribution. Among site-specific functions, the hormone has been suggested to be involved in uterine physiology. However, molecular analysis of the vitamin D system in normal endometrium throughout the menstrual cycle as well as its regulation in the context of endometrial physiological and pathological events have received very limited attention. Thus, we have studied expression, localization and regulation of 1 -OHase in human cycling and early pregnant endometrium. The capacity for 1 -hydroxylation and the presence of vitamin D receptor in endometrial cells have also been evaluated. The functional significance of these findings has been tested by evaluating gene expression of the catabolic enzyme, vitamin D 24-hydroxylase, and of the adhesion protein, osteopontin. Finally, to verify any potential dysfunction of the vitamin D system in endometriosis, a reproductive disease characterized by immune-mediated anomalies, we have analyzed expression of 1 -OHase in both eutopic and ectopic endometrium of affected patients. Results obtained showed that the active form of the 1 -OHase gene was expressed in human endometrial stromal cells independent of the cycle phase but with a significant increase in early pregnant decidua. A similar profile was observed for the protein, which was abundantly expressed in the cytoplasm of both endometrial stroma and epithelial glands. Both cycling and early pregnant endometrial cells also expressed the vitamin D receptor. In the same cells, 1 -OHase mRNA levels were significantly stimulated by the pro-inflammatory cytokine interleukin (IL)-1 (50 and 500 pg/ml) while addition of the active form of the hormone could modulate both CYP24 and osteopontin gene expression. The 1 -OHase gene was also expressed in ectopic endometrium and its levels were increased in proliferative phase cultures derived from patients with endometriosis. Human cycling endometrium may be included among the extrarenal sites able to synthesize vitamin D. The IL-1 −mediated induction of 1 -OHase gene and the hormonal modulation of osteopontin support a role for the hormone in the immunological mechanisms underlying uterine function. Abnormalities of this system are present in endometriosis.

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Section: Discussionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

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Cycling and early pregnant endometrium as a site of regulated expression of the vitamin D system

Viganò

Lattuada

Mangioni

et al. 2006

Journal of Molecular Endocrinology

171

119

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“…Using RNA differential display, Nie et al (13) identified that the CaBP-d9k gene was highly regulated in the mouse uterus in association with implantation. Its expression increases dramatically before implantation (13,14).…”

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confidence: 99%

Endometrial calbindins are critical for embryo implantation: Evidence fromin vivouse of morpholino antisense oligonucleotides

Luu

Nie

Salamonsen

2004

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

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The endometrium is receptive to embryo implantation only for a short period in each reproductive cycle: development of receptivity requires alterations in endometrial gene expression. Calbindin (CaBP)-d9k and CaBP-d28k are related proteins containing EF hand motifs that have a high affinity for Ca 2؉ . We previously demonstrated that endometrial expression of CaBP-d9k mRNA is highly regulated during implantation in the mouse. This project aimed to determine the temporal and spatial expression of both CaBP proteins during early pregnancy and to establish whether they are necessary for blastocyst implantation. CaBP-d28k protein, like CaBP-d9k, was up-regulated in the endometrial epithelium just before implantation but disappeared at implantation sites after attachment. By the judicious intrauterine injection of morpholino oligonucleotides (MO) against CaBP-d9k into WT and CaBP-d28k null mice just before implantation, we selectively eliminated one or both CaBPs from the uterine epithelium. Implantation was blocked only when both CaBP-d9k and CaBP-d28k were absent: treated WT mice and untreated CaBP-d28k null mice were fertile. Furthermore, the effect on implantation was highly dependent on the timing of injection of MO. This report examining the function of implantation-related genes in the uterus using MO demonstrates that this technique is a highly effective means to specifically target uterine proteins in vivo. This study provides evidence for an absolute requirement for CaBPs during the early phase of embryo implantation, and thus that regulation of Ca 2؉ availability in the uterine environment of the implanting embryo is critical for successful implantation.

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“…These include genes encoding amphiregulin (Areg) (Das et al 1995), histidine decarboxylase (Hdc) (Paria et al 1998), homeo box A10 (Hoxa10) and homeo box A11 (Hoxa11) (Lim et al 1999), calcitonin (Calca) (Kumar et al 1998, calbindin-D9K (Nie et al 2000), Indian hedgehog (Ihh) (Takamoto et al 2002), hypoxia-inducible factor 1 (Hif1a; Daikoku et al 2003) and immuneresponsive gene 1 (Irg1) (Cheon et al 2003). These target genes have been identified by testing candidate genes (Das et al 1995), by differential library screening and by DNA microarray approaches (Cheon et al 2002, Takamoto et al 2002.…”

Section: Introductionmentioning

confidence: 99%

Steroid hormone regulation of Clca3 expression in the murine uterus

Ky²,

Lydon³

et al. 2006

Journal of Endocrinology

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Progesterone (P4) and its cognate receptor, the progesterone receptor (PGR), have important roles in the establishment and maintenance of pregnancy in the murine uterus. In previous studies, using high-density DNA microarray analysis, we identified a subset of genes whose expression is repressed by chronic P4-PGR activation in the uterus. The Clca3 gene is one of the genes whose expression is the most significantly downregulated by P4 and PGR. In the present study, we performed real-time RT-PCR and in situ hybridization to investigate the regulation of Clca3 by P4 and determine the pattern of expression of Clca3 in the uterus during early pregnancy. This analysis shows that Clca3 mRNA transcripts were detected in the luminal and glandular epithelium of the pseudopregnant uterus at day 0·5 and that the expression of Clca3 was not detected after day 3·5. P4 represses Clca3 mRNA synthesis in the luminal epithelial and glandular epithelial cells of the uterus in ovariectomized wild-type mice, but not in Pgr knockout (PRKO) mice. Conversely, estrogen (E2) induces Clca3 expression in the luminal epithelium and glandular epithelium, and this induction was repressed by P4 in the murine uterus. Analysis of the promoter region of Clca3 by in silico and transient transfection analysis in HEC-1A cells identified the regulation of Clca3 by estrogen receptor-alpha (ESR1) within the first 528 bp of 5 -flanking region of the Clca3 gene. Our studies identified Clca3 as a novel downregulated gene of PGR that is a direct target of E2 regulation.

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Complex Regulation of Calcium-Binding Protein D9k (Calbindin-D9k) in the Mouse Uterus During Early Pregnancy and at the Site of Embryo Implantation1

Cited by 58 publications

References 49 publications

Cycling and early pregnant endometrium as a site of regulated expression of the vitamin D system

Cycling and early pregnant endometrium as a site of regulated expression of the vitamin D system

Endometrial calbindins are critical for embryo implantation: Evidence fromin vivouse of morpholino antisense oligonucleotides

Steroid hormone regulation of Clca3 expression in the murine uterus

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