Conditional loss of ERK1 and ERK2 results in abnormal placentation and delayed parturition in the mouse

Extracellular-signal-regulated kinases (ERK) 1 and 2 regulate many aspects of the hypothalamic-pituitary-gonadal axis. We sought to understand the role of ERK1/2 signaling in cells expressing a Cre allele regulated by the endogenous GnRHR promoter (GRIC-ERKdko). Adult female GRIC-ERKdko mice were hy...

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Bibliographic Details
Published in:	Scientific reports Vol. 9; no. 1; pp. 9641 - 13
Main Authors:	Brown, Jessica L., Sones, Jennifer L., Angulo, Cynthia N., Abbott, Keelin, Miller, Andrew D., Boehm, Ulrich, Roberson, Mark S.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 03-07-2019 Nature Publishing Group
Subjects:	13 13/95 631/208/135 631/443/494 631/80/86/820 64 64/60 82/80 96 96/95 Animals Apoptosis Biosynthesis Decidua Estrus cycle Extracellular signal-regulated kinase Female Females Fetal Growth Retardation - etiology Fetal Growth Retardation - pathology Genes Gestation Gonadotropins Histopathology Hormones Humanities and Social Sciences Hypothalamic-pituitary-gonadal axis Hypothalamus Implantation Infant mortality Infertility Kinases Mice Mice, Knockout Mitogen-Activated Protein Kinase 1 - physiology Mitogen-Activated Protein Kinase 3 - physiology Mortality mRNA multidisciplinary Neonates Ovulation Parturition Pituitary Pituitary (anterior) Pituitary-gonadal axis Placenta Placenta - pathology Placentation Pregnancy Recombination Science Science (multidisciplinary) Uterus Veterinary colleges Veterinary medicine
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Summary:	Extracellular-signal-regulated kinases (ERK) 1 and 2 regulate many aspects of the hypothalamic-pituitary-gonadal axis. We sought to understand the role of ERK1/2 signaling in cells expressing a Cre allele regulated by the endogenous GnRHR promoter (GRIC-ERKdko). Adult female GRIC-ERKdko mice were hypogonadotropic and anovulatory. Gonadotropin administration and mating led to pregnancy in one-third of the ERKdko females. Litters from ERKdko females and pup weights were reduced coincident with delayed parturition and 100% neonatal mortality. Based on this, we examined Cre expression in implantation sites as a potential mechanism. GnRHR mRNA levels at e10.5 and e12.5 were comparable to pituitary levels from adult female mice at proestrus and GnRHR mRNA in decidua was enriched compared to whole implantation site. In vivo studies confirmed recombination in decidua, and GRIC-ERKdko placentas showed reduced ERK2 expression. Histopathology revealed abnormalities in placental architecture in the GRIC-ERKdko animals. Regions of apoptosis at the decidual/uterine interface at e18.5 were observed in control animals but apoptotic tone in these regions was reduced in ERKdko animals. These studies support a potential model of ERK-dependent signaling within the implantation site leading to loss of placental architecture and mis-regulation of apoptotic events at parturition occurring coincident with prolonged gestation and neonatal mortality.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2045-2322 2045-2322
DOI:	10.1038/s41598-019-45997-0