p38-Mitogen Activated Kinases Mediate a Developmental Regulatory Response to Amino Acid Depletion and Associated Oxidative Stress in Mouse Blastocyst Embryos

Pablo Bora; Vasanth Thamodaran; Andrej Šušor; Alexander W Bruce

doi:10.3389/fcell.2019.00276

p38-Mitogen Activated Kinases Mediate a Developmental Regulatory Response to Amino Acid Depletion and Associated Oxidative Stress in Mouse Blastocyst Embryos

Front Cell Dev Biol. 2019 Nov 8:7:276. doi: 10.3389/fcell.2019.00276. eCollection 2019.

Authors

Pablo Bora¹, Vasanth Thamodaran¹, Andrej Šušor², Alexander W Bruce¹

Affiliations

¹ Laboratory of Early Mammalian Developmental Biology, Department of Molecular Biology and Genetics, Faculty of Science, University of South Bohemia, České Budějovice, Czechia.
² Laboratory of Biochemistry and Molecular Biology of Germ Cells, Institute of Animal Physiology and Genetics CAS, v. v. i., Liběchov, Czechia.

Abstract

Maternal starvation coincident with preimplantation development has profound consequences for placental-fetal development, with various identified pathologies persisting/manifest in adulthood; the 'Developmental Origin of Health and Disease' (DOHaD) hypothesis/model. Despite evidence describing DOHaD-related incidence, supporting mechanistic and molecular data relating to preimplantation embryos themselves are comparatively meager. We recently identified the classically recognized stress-related p38-mitogen activated kinases (p38-MAPK) as regulating formation of the extraembryonic primitive endoderm (PrE) lineage within mouse blastocyst inner cell mass (ICM). Thus, we wanted to assay if PrE differentiation is sensitive to amino acid availability, in a manner regulated by p38-MAPK. Although blastocysts appropriately mature, without developmental/morphological or cell fate defects, irrespective of amino acid supplementation status, we found the extent of p38-MAPK inhibition induced phenotypes was more severe in the absence of amino acid supplementation. Specifically, both PrE and epiblast (EPI) ICM progenitor populations remained unspecified and there were fewer cells and smaller blastocyst cavities. Such phenotypes could be ameliorated, to resemble those observed in groups supplemented with amino acids, by addition of the anti-oxidant NAC (N-acetyl-cysteine), although PrE differentiation deficits remained. Therefore, p38-MAPK performs a hitherto unrecognized homeostatic early developmental regulatory role (in addition to direct specification of PrE), by buffering blastocyst cell number and ICM cell lineage specification (relating to EPI) in response to amino acid availability, partly by counteracting induced oxidative stress; with clear implications for the DOHaD model.

Keywords: cell fate; developmental origin of health and disease (DOHaD); mouse blastocyst; oxidative stress; p38-mitogen activated kinases; primitive endoderm.