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.
Highlights
The formation of the peri-implantation stage mouse blastocyst represents the culmination of the preimplantation period in which three distinct cell lineages emerge
We have previously reported a role for p38-mitogen activated kinases a/β, employing pharmacological inhibition, in regulating primitive endoderm (PrE) differentiation within mouse blastocyst inner cell mass (ICM) (Thamodaran and Bruce, 2016). p38MAPK was found to act during the early stages of ICM maturation, downstream of fibroblast growth factor (FGF) signaling, permitting PrE progenitors to resolve their uncommitted fate [as is characteristic of the majority of nascent ICM cells at E3.5 (Chazaud et al, 2006)] and functionally diverge and segregate from the EPI lineage (Thamodaran and Bruce, 2016)
P38-MAPK belong to the wider family of serine-threonine and tyrosine kinases, regulating a wide variety of cellular functions (Cargnello and Roux, 2011), they differ from the other family members, such as extra-cellular regulated kinases [e.g., extra-cellular regulated kinases 1/2 (ERK1/2) – themselves implicated in FGF-mediated PrE differentiation at a developmental point succeeding that identified for p38-MAPK (Nichols et al, 2009; Yamanaka et al, 2010; Frankenberg et al, 2011; Kang et al, 2013; Thamodaran and Bruce, 2016)] in that they are classically known to be activated by extracellular stress stimuli; for example pro-inflammatory cytokines, U.V. radiation and physical stress, rather than liganded growth-factor associated receptor tyrosine kinases (Remy et al, 2010)
Summary
The formation of the peri-implantation stage mouse blastocyst (by embryonic day 4.5/E4.5) represents the culmination of the preimplantation period in which three distinct cell lineages emerge. P38-MAPK (and their related paralogs, p38γ/δ) belong to the wider family of serine-threonine and tyrosine kinases, regulating a wide variety of cellular functions (Cargnello and Roux, 2011), they differ from the other family members, such as extra-cellular regulated kinases [e.g., ERK1/2 – themselves implicated in FGF-mediated PrE differentiation at a developmental point succeeding that identified for p38-MAPK (Nichols et al, 2009; Yamanaka et al, 2010; Frankenberg et al, 2011; Kang et al, 2013; Thamodaran and Bruce, 2016)] in that they are classically known to be activated by extracellular stress stimuli; for example pro-inflammatory cytokines, U.V. radiation and physical stress, rather than liganded growth-factor associated receptor tyrosine kinases (Remy et al, 2010) It is estimated activated p38-mitogen activated kinases in general are able to phosphorylate and regulate between 200 and 300 cellular substrates (Cuadrado and Nebreda, 2010; Trempolec et al, 2013; Hornbeck et al, 2019). In the context of this study, there is precedent for the involvement of active p38-MAPK in amino acid (AA) signaling (Casas-Terradellas et al, 2008) and regulation of autophagy (Webber, 2010), in other nonembryo models
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