The lats gene has been identified as a tumour suppressor in Drosophila melanogaster using mosaic screens. Mosaic flies carrying somatic cells that are mutant for lats develop large tumours in many organs. The human LATS1 homologue rescues embryonic lethality and inhibits tumour growth in lats mutant flies, demonstrating the functional conservation of this gene. Biochemical and genetic analyses have revealed that LATS1 functions as a negative regulator of CDC2 (ref. 3). These data suggest that mammalian LATS1 may have a role in tumorigenesis. To elucidate the function of mammalian LATS1, we have generated Lats1-/- mice. Lats1-/- animals exhibit a lack of mammary gland development, infertility and growth retardation. Accompanying these defects are hyperplastic changes in the pituitary and decreased serum hormone levels. The reproductive hormone defects of Lats1-/- mice are reminiscent of isolated LH-hypogonadotropic hypogonadism and corpus luteum insufficiency in humans. Furthermore, Lats1-/- mice develop soft-tissue sarcomas and ovarian stromal cell tumours and are highly sensitive to carcinogenic treatments. Our data demonstrate a role for Lats1 in mammalian tumorigenesis and specific endocrine dysfunction.
The molecular mechanisms that underlie embryo implantation are poorly understood. Under the control of sex steroids, uterine endometrium undergoes tremendous, yet tightly controlled, proliferation in each estrous cycle to facilitate implantation; disorders of endometrial proliferation underlie several uterine diseases. We have previously identified the Emx2 gene as a transcriptional target of HOXA10 regulation in the reproductive tract. Here we report the function of Emx2 in murine implantation and regulation of endometrial proliferation. We transfected mice on d 2 post coitus with pcDNA3.1/Emx2, Emx2 antisense, or respective controls consisting of empty pcDNA3.1 or a random order oligonucleotide by intrauterine lipofection. Increased expression of Emx2 reduced average implantation rate by approximately 40% (P = 0.00006) resulting in an average number of implanted embryos per litter of 13.7 in the control group to 8.2 in the pcDNA3.1/Emx2-treated group. Neither treatment altered the number of mice attaining pregnancy with at least one embryo. Decreased Emx2 expression did not alter litter size. Neither treatment affected the birth weight of the pups. To elucidate potential mechanisms through which Emx2-regulated reproduction, markers of endometrial differentiation, proliferation, and apoptosis were assessed. Increased Emx2 expression significantly decreased endometrial cell proliferating cell nuclear antigen expression and 5'-bromo-2' deoxyuridine incorporation. Markers of stromal cell differentiation (IGF binding protein-1, prolactin), epithelial differentiation (calcitonin), and apoptosis (activated caspase3) were unchanged. In human endometrial epithelial cells in vitro, Emx2 reduced cell number indicating diminished proliferation. Emx2 controls mammalian reproduction by adjusting endometrial cell proliferation without effecting differentiation. Regulated uterine Emx2 expression is necessary during reproduction for maximal implantation and litter size.
Objective-To characterize human endometrial HOXA10 expression in patients using copper intrauterine devices (IUD).Design-Case-control study. Setting-Academic medical center Patient(s)-Women using copper IUDInterventions(s)-Immunohistochemical analysis of endometrial HOXA10 expression in biopsies obtained from 24 women using copper Paraguard T380A as well as in biopsies obtained from 10 normal cycling women who were not using IUD or hormonal contraceptives. Main Outcome Measure(s)-Endometrial HOXA10 expression.Result(s)-Endometrial HOXA10 expression was markedly decreased in biopsies obtained from women using IUD contraceptive when compared to controls. The mean H score for endometrial stromal cell HOXA10 expression in biopsies obtained from women using Paraguard IUD was 0.21 compared to 2.2 in the control endometrial biopsies (P<0.001). Endometrial glandular expression of HOXA10 was absent in all IUD users. Conclusion(s)-Decreasedendometrial HOXA10 expression was apparent in women who use a copper IUD. Expression of HOXA10 is essential for endometrial receptivity. A novel mechanism of copper IUD action involves suppression of genes required for endometrial receptivity. The dramatic decrease of endometrial HOXA10 in response to IUD use may contribute to contraceptive efficacy.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.