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Loss of receptor activity-modifying protein 2 in mice causes placental dysfunction and alters PTH1R regulation

Receptor activity-modifying protein 2 (Ramp2) is a single-pass transmembrane protein that heterodimerizes with several family B G-protein coupled receptors to alter their function. Ramp2 has been primarily characterized in association with calcitonin receptor-like receptor (Calcrl, CLR), forming the...

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Autores principales: Kadmiel, Mahita, Matson, Brooke C., Espenschied, Scott T., Lenhart, Patricia M., Caron, Kathleen M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519170/
https://www.ncbi.nlm.nih.gov/pubmed/28727763
http://dx.doi.org/10.1371/journal.pone.0181597
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author Kadmiel, Mahita
Matson, Brooke C.
Espenschied, Scott T.
Lenhart, Patricia M.
Caron, Kathleen M.
author_facet Kadmiel, Mahita
Matson, Brooke C.
Espenschied, Scott T.
Lenhart, Patricia M.
Caron, Kathleen M.
author_sort Kadmiel, Mahita
collection PubMed
description Receptor activity-modifying protein 2 (Ramp2) is a single-pass transmembrane protein that heterodimerizes with several family B G-protein coupled receptors to alter their function. Ramp2 has been primarily characterized in association with calcitonin receptor-like receptor (Calcrl, CLR), forming the canonical receptor complex for the endocrine peptide adrenomedullin (Adm, AM). However, we previously demonstrated that Ramp2(+/-) female mice display a constellation of endocrine-related phenotypes that are distinct from those of Adm(+/-) and Calcrl(+/-) mice, implying that RAMP2 has physiological functions beyond its canonical complex. Here, we localize Ramp2 expression in the mouse placenta, finding that Ramp2 is robustly expressed in the fetal labyrinth layer, and then characterize the effects of loss of Ramp2 on placental development. Consistent with the expression pattern of Ramp2 in the placenta, Ramp2(-/-) placentas have a thinner labyrinth layer with significantly fewer trophoblast cells secondary to a reduction in trophoblast proliferation. We also find that absence of Ramp2 leads to failed spiral artery remodeling unaccompanied by changes in the uterine natural killer cell population. Furthermore, we assess changes in gene expression of other RAMP2-associated G-protein coupled receptors (GPCRs), concluding that Ramp2 loss decreases parathyroid hormone 1 receptor (Pthr1) expression and causes a blunted response to systemic parathyroid hormone (PTH) administration in mice. Ultimately, these studies provide in vivo evidence of a role for RAMP2 in placental development distinct from the RAMP2-CLR/AM signaling paradigm and identify additional pathways underlying the endocrine and fertility defects of the previously characterized Ramp2 heterozygous adult females.
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spelling pubmed-55191702017-08-07 Loss of receptor activity-modifying protein 2 in mice causes placental dysfunction and alters PTH1R regulation Kadmiel, Mahita Matson, Brooke C. Espenschied, Scott T. Lenhart, Patricia M. Caron, Kathleen M. PLoS One Research Article Receptor activity-modifying protein 2 (Ramp2) is a single-pass transmembrane protein that heterodimerizes with several family B G-protein coupled receptors to alter their function. Ramp2 has been primarily characterized in association with calcitonin receptor-like receptor (Calcrl, CLR), forming the canonical receptor complex for the endocrine peptide adrenomedullin (Adm, AM). However, we previously demonstrated that Ramp2(+/-) female mice display a constellation of endocrine-related phenotypes that are distinct from those of Adm(+/-) and Calcrl(+/-) mice, implying that RAMP2 has physiological functions beyond its canonical complex. Here, we localize Ramp2 expression in the mouse placenta, finding that Ramp2 is robustly expressed in the fetal labyrinth layer, and then characterize the effects of loss of Ramp2 on placental development. Consistent with the expression pattern of Ramp2 in the placenta, Ramp2(-/-) placentas have a thinner labyrinth layer with significantly fewer trophoblast cells secondary to a reduction in trophoblast proliferation. We also find that absence of Ramp2 leads to failed spiral artery remodeling unaccompanied by changes in the uterine natural killer cell population. Furthermore, we assess changes in gene expression of other RAMP2-associated G-protein coupled receptors (GPCRs), concluding that Ramp2 loss decreases parathyroid hormone 1 receptor (Pthr1) expression and causes a blunted response to systemic parathyroid hormone (PTH) administration in mice. Ultimately, these studies provide in vivo evidence of a role for RAMP2 in placental development distinct from the RAMP2-CLR/AM signaling paradigm and identify additional pathways underlying the endocrine and fertility defects of the previously characterized Ramp2 heterozygous adult females. Public Library of Science 2017-07-20 /pmc/articles/PMC5519170/ /pubmed/28727763 http://dx.doi.org/10.1371/journal.pone.0181597 Text en © 2017 Kadmiel et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Kadmiel, Mahita
Matson, Brooke C.
Espenschied, Scott T.
Lenhart, Patricia M.
Caron, Kathleen M.
Loss of receptor activity-modifying protein 2 in mice causes placental dysfunction and alters PTH1R regulation
title Loss of receptor activity-modifying protein 2 in mice causes placental dysfunction and alters PTH1R regulation
title_full Loss of receptor activity-modifying protein 2 in mice causes placental dysfunction and alters PTH1R regulation
title_fullStr Loss of receptor activity-modifying protein 2 in mice causes placental dysfunction and alters PTH1R regulation
title_full_unstemmed Loss of receptor activity-modifying protein 2 in mice causes placental dysfunction and alters PTH1R regulation
title_short Loss of receptor activity-modifying protein 2 in mice causes placental dysfunction and alters PTH1R regulation
title_sort loss of receptor activity-modifying protein 2 in mice causes placental dysfunction and alters pth1r regulation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519170/
https://www.ncbi.nlm.nih.gov/pubmed/28727763
http://dx.doi.org/10.1371/journal.pone.0181597
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