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Molecular Biology of the Stress Response in the Early Embryo and its Stem Cells

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Cell Signaling During Mammalian Early Embryo Development

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 843))

Abstract

Stress is normal during early embryogenesis and transient, elevated stress is commonplace. Stress in the milieu of the peri-implantation embryo is a summation of maternal hormones, and other elements of the maternal milieu, that signal preparedness for development and implantation. Examples discussed here are leptin, adrenaline, cortisol, and progesterone. These hormones signal maternal nutritional status and provide energy, but also signal stress that diverts maternal and embryonic energy from an optimal embryonic developmental trajectory. These hormones communicate endocrine maternal effects and local embryonic effects although signaling mechanisms are not well understood. Other in vivo stresses affect the embryo such as local infection and inflammation, hypoxia, environmental toxins such as benzopyrene, dioxin, or metals, heat shock, and hyperosmotic stress due to dehydration or diabetes. In vitro, stresses include shear during handling, improper culture media and oxygen levels, cryopreservation, and manipulations of the embryo to introduce sperm or mitochondria. We define stress as any stimulus that slows stem cell accumulation or diminishes the ability of cells to produce normal and sufficient parenchymal products upon differentiation. Thus stress deflects downwards the normal trajectories of development, growth and differentiation. Typically stress is inversely proportional to embryonic developmental and proliferative rates, but can be proportional to induction of differentiation of stem cells in the peri-implantation embryo. When modeling stress it is most interesting to produce a ‘runting model’ where stress exposures slow accumulation but do not create excessive apoptosis or morbidity. Windows of stress sensitivity may occur when major new embryonic developmental programs require large amounts of energy and are exacerbated if nutritional flow decreases and removes energy from the normal developmental programs and stress responses. These windows correspond to zygotic genome activation, the large mRNA program initiated at compaction, ion pumping required for cavitation, the differentiation of the first lineages, integration with the uterine environment at implantation, rapid proliferation of stem cells, and production of certain lineages which require the highest energy and are most sensitive to mitochondrial inhibition. Stress response mechanisms insure that stem cells for the early embryo and placenta survive at lower stress exposures, and that the organism survives through compensatory and prioritized stem cell differentiation, at higher stress exposures. These servomechanisms include a small set of stress enzymes from the 500 protein kinases in the kinome; the part of the genome coding for protein kinases that hierarchically regulate the activity of other proteins and enzymes. Important protein kinases that mediate the stress response of embryos and their stem cells are SAPK, p38MAPK, AMPK, PI3K, Akt, MEK1/2, MEKK4, PKA, IRE1 and PERK. These stress enzymes have cytosolic function in cell survival at low stress exposures and nuclear function in modifying transcription factor activity at higher stress exposures. Some of the transcription factors (TFs) that are most important in the stress response are JunC, JunB, MAPKAPs, ATF4, XBP1, Oct1, Oct4, HIFs, Nrf2/KEAP, NFKB, MT1, Nfat5, HSF1/2 and potency-maintaining factors Id2, Cdx2, Eomes, Sox2, Nanog, Rex1, and Oct4. Clearly the stress enzymes have a large number of cytosolic and nuclear substrates and the TFs regulate large numbers of genes. The interaction of stress enzymes and TFs in the early embryo and its stem cells are a continuing central focus of research. In vitro regulation of TFs by stress enzymes leads to reprogramming of the stem cell when stress diminishes stem cell accumulation. Since more differentiated product is produced by fewer cells, the process compensates for fewer cells. Coupled with stress-induced compensatory differentiation of stem cells is a tendency to prioritize differentiation by increasing the first essential lineage and decreasing later lineages. These mechanisms include stress enzymes that regulate TFs and provide stress-specific, shared homeostatic cellular and organismal responses of prioritized differentiation.

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Notes

  1. 1.

    Acronyms and abbreviations used

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Acknowledgments

This was supported by grants to DAR from NICHD, NIH, (1R03HD06143101, R01HD40972A) and from the Wayne State University Office of the Vice President for Research and to the Mary Iacobelli for the Endowed Chair for EEP.

Author information

Authors and Affiliations

  1. CS Mott Center for Human Growth and Development, Detroit, MI, USA

    Yu Yang, Zhongliang Jiang & Daniel A. Rappolee

  2. Department of Ob/Gyn, REI Division, Wayne State University School of Medicine, Detroit, MI, USA

    Elizabeth E. Puscheck, Awoniyi O. Awonuga, Zhongliang Jiang & Daniel A. Rappolee

  3. Program for Reproductive Sciences, Detroit, MI, USA

    Yu Yang & Daniel A. Rappolee

  4. Department of Physiology, Wayne State University School of Medicine, Detroit, MI, USA

    Yu Yang & Daniel A. Rappolee

  5. Institute for Environmental Health and Safety, Detroit, MI, USA

    Daniel A. Rappolee

  6. Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA

    Daniel A. Rappolee

  7. Department of Biology, University of Windsor, N9B 3P4, Windsor, ON, Canada

    Daniel A. Rappolee

  8. CS Mott Center for Human Growth and Development, Wayne State University School of Medicine, 48201, Detroit, 275 East HancockMI, USA

    Daniel A. Rappolee

Authors
  1. Elizabeth E. Puscheck
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  2. Awoniyi O. Awonuga
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  3. Yu Yang
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  4. Zhongliang Jiang
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  5. Daniel A. Rappolee
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Corresponding author

Correspondence to Daniel A. Rappolee .

Editor information

Editors and Affiliations

  1. Hertford Building, Hull York Medical School University of Hull, Hull, United Kingdom

    Henry J. Leese

  2. St. Mary's Hospital Department of Reproductive Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom

    Daniel R. Brison

Glossary

Acronyms and abbreviations used

AMPK

AMP-activated protein kinase heterotrimer stress kinase (aka Prkaa1/2 is catalytic subunit)

ART

assisted reproductive technology

ATF3/4/6

activating transcription factor 3/4/6 are members of the ATF/CREB family of transcription factors

ATP

adenosine triphosphate

CaMKK

calmodulin kinase kinase

Cdx2

caudal-type homeodomain protein 2 transcription factor

CHOP10

C/EBP homologous protein-10, aka growth arrest and DNA damage/GADD153

CpG

cytosine guanosine islands

DDIT3

DNA damage inducible transcript 3

DNA

deoxyribonucleic acid

dsRNA

double strand RNA

eIF2α

elongation initiation factor 2 alpha

EMT

epithelial mesenchymal transition

ERRβ

estrogen receptor related, beta transcription factor

ER stress

endoplasmic reticulum sensed stress

ERK1/3/5

extracellular receptor kinase 1/3/5

ESC

embryonic stem cells

FGF4

fibroblast growth factor 4

Foxo

Fox, A subclass of winged helix DNA-binding proteins (related to Forkhead family).

G1/S

Cell cycle Gap 1 to synthesis phase, aka Start

Gastrulation

formation and patterning of the three definitive embryo germ cell layers; endoderm, mesoderm, and ectoderm.

GCM1

glial cells missing 1 transcription factor

GCN2

germinal cell nucleus 1

Genotoxic stress

nuclear stress affecting DNA integrity

Hand1

heart and mesoderm inducer transcription factor

hCG

human chorionic gonadotropin

HDAC

histone deacetylase enzyme

HIF1

hypoxia inducible factor 1 transcription factor

HIF1

hypoxia inducible factor 1 transcription factor

HRI

Heme-Regulated Inhibitor

HSD2

11β-hydroxysteroid dehydrogenase type

HSF1

heat shock factor-1

HSP70.1/90

heat shock proteins 22/68/70.1

HuR

Hu protein R (mRNA stabilizing protein)

ICM

inner cell mass of the blastocyst, precursor stem cells of extraembryonic endoderm and mesoderm and of the three germ cell layers at gastrulation.

Id2

Inhibitor of differentiation 2 dominant negative transcription factor

iPS cells

inducible pluripotent stem cells

IRE1

Inositol-requiring enzyme 1; ER transmembrane kinase/ribonuclease

ISH

In situ hybridization

IVF

in vitro fertilization

JunB/C

Jun transcription factor in the AP1 family

KSOM

Potassium (K) Simplex optimized media. Least stressful media.

LKB1

liver kinase B

MDM2

Mouse double minute 2

MRP

Maternal recognition of pregnancy Secreted signal from the mammalian conceptus to keep the implantation site prepared for invasion by and nutrition or the conceptus

M16

Preimplantation culture media, stressful

MAPK/ERK1/3

mitogen-activated protein kinase

MEK1/2

mitogen-activated protein kinase kinase kinase 1/2 tyrosine threonine dual protein kinase

MEKK4

mitogen-activated protein kinase kinase kinase 4 tyrosine threonine dual protein kinase that activates SAPK and p38MAPK

mRNA

messenger ribonucleic acid

MT1

metal regulatory transcription factor 1

NACHT

(see NALP5) Nalp5, leucine rich repeat and PYD containing 5

NaCl

sodium chloride

NALP5/Mater

Nacht Domain-, Leucine-Rich Repeat-, and PYD-Containing Protein 5/maternal antigen that embryos require

Nfat5

Nuclear factor of activated T-cells

NRF2

nuclear factor erythroid-derived factor 2 (aka KEAP2)

Nuclear stress responses

see genotoxic stress

P38MAPK

p38 mitogen-activated protein kinase (aka MAPK11/12/13/14)

P53

Tumor suppressor factor, (aka TRP53)

PAF

Platelet activating factor

PERK

Eukaryotic translation initiation factor 2-alpha kinase 3, aka PRKR-like endoplasmic reticulum kinase, and aka protein kinase R (PKR)-like endoplasmic reticulum kinase,

PI3K

Phosphoinositol 1,3 kinase

PL1

Placental lactogen 1 rodent hormone produced by TGC (aka chorionic sommatomammotropin, CSH1)

PKA

protein kinase A

PKM2

pyruvate kinase 2 embryonic form

PKR

protein kinase RNA

PLK4

polo-like kinase (PLK)4

PLPA

Prolactin-like protein A

PPAR

Peroxisome proliferator-activated receptor transcription factor

Ppp1r15a/b

Protein phosphatase 1 subunit regulatory subunit 15a/b

PRC2

polycombs regulatory complex 2

Oct4

octamer binding transcription factor 4 (aka Pou5f1)

SAPK

stress-activated protein kinase

TF

Transcription factors

TGC

Trophoblast giant cell

TNFα

tumor necrosis factor alpha

TSA

trichostatin A

TSC

trophoblast stem cell

TSC2

tuberous sclerosis complex

UNC2

uncoupling protein-2

XBP1

X-box binding protein 1/activating transcription factor 4/6)

XEN

extraembryonic endoderm

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Puscheck, E., Awonuga, A., Yang, Y., Jiang, Z., Rappolee, D. (2015). Molecular Biology of the Stress Response in the Early Embryo and its Stem Cells. In: Leese, H., Brison, D. (eds) Cell Signaling During Mammalian Early Embryo Development. Advances in Experimental Medicine and Biology, vol 843. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-2480-6_4

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