Muscle Segment Homeobox Genes Direct Embryonic Diapause by Limiting Inflammation in the Uterus.
Embryonic diapause is a reproductive strategy widespread in the animal kingdom. This phenomenon is defined by a temporary arrest in blastocyst growth and metabolic activity within a quiescent uterus without implantation until the environmental and maternal milieu become favorable for pregnancy to progress. We found that uterine Msx expression persists during diapause across species; their inactivation in the mouse uterus results in termination of diapause with the development of implantation-like responses ("pseudoimplantation") that ultimately succumbed to resorption. To understand the cause of this failure, we compared proteome profiles between floxed and Msx-deleted uteri. In deleted uteri, several functional networks, including transcription/translation, ubiquitin-proteasome, inflammation, and endoplasmic reticulum stress, were dysregulated. Computational modeling predicted intersection of these pathways on an enhanced inflammatory signature. Further studies showed that this signature was reflected in increased phosphorylated IκB levels and nuclear NFκB in deleted uteri. This was associated with enhanced proteasome activity and endoplasmic reticulum stress. Interestingly, treatment with anti-inflammatory glucocorticoid (dexamethasone) reduced the inflammatory signature with improvement of the diapause phenotype. These findings highlight an unexpected role of uterine Msx in limiting aberrant inflammatory responses to maintain embryonic diapause.
From the Division of Reproductive Sciences and.
Jeeyeon
J
Cha
the Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99354.
Kristin E
KE
Burnum-Johnson
From the Division of Reproductive Sciences and.
Amanda
A
Bartos
From the Division of Reproductive Sciences and.
Yingju
Y
Li
the Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99354.
Erin S
ES
Baker
the Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99354, the Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon 97331.
Susan C
SC
Tilton
the Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99354.
Bobbie-Jo M
BJ
Webb-Robertson
From the Division of Reproductive Sciences and.
Paul D
PD
Piehowski
the Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99354.
Matthew E
ME
Monroe
Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039.
Anil G
AG
Jegga
the Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 Japan, and.
Shigeo
S
Murata
the Department of Obstetrics and Gynecology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655 Japan.
Yasushi
Y
Hirota
From the Division of Reproductive Sciences and sk.dey@cchmc.org.
Sudhansu K
SK
Dey
D000818:Animals; D047108:Embryonic Development / Q000235:genetics*; D005260:Female; D005801:Genes, Homeobox; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D007249:Inflammation / Q000235:genetics*; D051957:MSX1 Transcription Factor / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000473:pathology*; D011247:Pregnancy; D014599:Uterus / Q000378:metabolism / Q000473:pathology*
D018398:Homeodomain Proteins; D051957:MSX1 Transcription Factor; C084119:MSX2 protein; C484084:Msx1 protein, mouse
Msx genes; NF-kappa B (NF-KB); cyclooxygenase (COX); embryonic diapause; implantation; inflammation; mouse; pregnancy; proteomics; uterus