there is increasing evidence linking endoplasmic reticulum ( er ) stress coping responses with the development of diseases .
this is not surprising , given that the er is a multifunctional essential organelle in eukaryotic cells ; it functions as the critical entrance to the secretory pathways , and is also a regulator of ca homeostasis , as well as protein and lipid synthesis , all of which are highly sensitive to a variety of environmental , physiological , and pathophysiological conditions .
the er is also closely associated with all cellular organelles , and therefore , capable of driving sophisticated mechanisms of intracellular signaling , including activation of transcriptional processes , ca mobilization , and influencing energy metabolism . in this review
, we briefly summarize the er stress coping responses , particularly the unfolded protein response ( upr ) , and discuss the potential role of upr as a physiologically relevant pathway in supporting and controlling proper embryonic development .
it impairs er functions such as protein folding and the heat shock response , and leads to altered ca levels and nutrient starvation .
activation of er stress can result in the buildup of misfolded proteins in the er and activation of the upr as a coping strategy ( figure 1 ) .
the upr involves distinct components designed to reestablish the protein synthesis machinery ( figure 1 ) .
these include ( 1 ) translational attenuation to arrest the entry of new proteins into the er ; ( 2 ) transcriptional activation of genes encoding proteins involved in protein folding to assist the maturation of proteins ; ( 3 ) transcriptional activation of genes for components of the er - associated protein degradation ( erad ) system to decrease the number of misfolded proteins ; and if these are not successful , ( 4 ) activation of apoptotic pathways to eliminate defective cells .
three er transmembrane proteins : dsrna - activated protein kinase - like er kinase ( perk ) , activating transcription factor 6 ( atf6 ) , and inositol - requiring enzyme 1 ( ire1 ) , in combination with the er molecular chaperone immunoglobulin binding protein ( bip , also known as glucose - regulated protein [ grp ] 78 ) , compose the upr , an er stress coping response .
it is a monomeric , globular protein that functionally sorts and releases terminally misfolded substrates to the erad pathway . under non - stressed conditions grp78/bip interacts with ire , perk , and atf6 , but upon an increase in misfolded proteins
, grp78/bip is sequestered away from these inducers , leading to the activation of the upr .
release of grp78/bip from perk triggers its dimerization and autophosphorylation , followed by phosphorylation of eif2 , at ser , which inhibits protein synthesis by sequestering the trnamet responsible for initiating the translation of nascent protein ( figure 1 ) . during this period ,
atf4 transcriptional activity induces both pro - survival ( early ) and pro - apoptotic ( late ) transcriptional programs .
atf6 is an er transmembrane protein cleaved in the golgi . under non - stress conditions
when bip is sequestered away from atf6 , the atf6 is translocated to the golgi , where it undergoes cleavage by site-1 and site-2 proteases ( s1p and s2p ) ( figure 1 ) .
cleavage of atf6 produces a soluble basic leucine zipper ( bzip ) transcription factor ( cleaved atf6 ) that binds to er stress response elements ( erse - i and ii ) to induce transcriptional activation of er stress response genes .
atf6 can induce the expression upr - induced genes including grp78/bip , proteins involved in erad , and xbp1 mrna .
interestingly , er stress triggered by ca depletion induces the formation of a nascent , partially glycosylated form of atf6 with reduced interaction with calreticulin , and a faster rate of traversing the golgi , resulting in higher transactivation of atf6 gene targets . upon release of grp78/bip under stress conditions , ire1 homodimerizes , causing a conformational change that is transmitted across the membrane , leading to activation of its cytoplasmic kinase activity , autophosphorylation , and activation of its endoribonuclease activity ( figure 1 ) .
ire1 endoribonuclease activity cleaves 28s rrna and specific micrornas , inhibits protein synthesis , and also splices xbp1
the protein product from the sxbp1 variant binds to the specific promoter elements , erse , and upre , triggering transactivation upr responsive genes such as grp78/bip , calreticulin , and others , which are part of the protein folding quality control and degradation machinery .
one part of the cellular recovery system that is turned on by the upr is er - associated degradation ( erad ) .
there is tight regulation of the three arms of the upr with respect to the timing and response amplitude .
the activation of each arm of the upr is specific to the source of er stress and governs cell fate , supporting either an adaptive response ( cell survival ) or a maladaptive response ( cell death ) . under prolonged and irreversible er stress ,
, upr activates autophagy , a controlled self - degradation process that can promote cell survival by eliminating damaged cellular components .
the intensity , timing , and duration of the upr appear to be important in determining cell fate .
these observations suggest that er stress coping responses may also play an important role in the maintenance of physiological events associated with organ function and/or development .
although there is emerging evidence that activation of er stress coping responses , including upr , may play an important role in diverse human diseases , it is conceivable that these coping responses may also be critical under normal physiological conditions and during development .
interestingly , there exists a group of small molecules that may stabilize protein folding , prevent protein aggregation , and consequently affect the severity of upr activation .
the most studied of these molecules are synthetic - fatty acid derivative 4-phenylbutyric acid and the natural bile acid tauroursodeoxycholic acid ( tudca ) . although the precise mechanisms of their action are not clear at present , these compounds have a profound impact on many pathologies including obesity pathways , brain ischemic - reperfusion , photoreceptor pathology , and steatosis , to name a few .
these findings suggest that targeting er physiology and er stress signaling and stress - induced coping responses has therapeutic potential for treating diseases related to er stress .
the development of preimplantation embryos is under the influence of various hormones and growth factors that originate from maternal tissues and/or the embryo proper .
preimplantation embryos synthesize and secrete a wide range of hormones and growth factors that promote embryonic survival ; in the blastocyst stage , they increase in cell number via activation of transcription as well as protein synthesis . during this synthetic activity
, the embryos may experience an inherent level of er stress   and consequently activate specific coping responses to recover homeostasis and support development or death .
for example , in the mouse , the upr contributes to preimplantation embryo death in the ddk syndrome , suggesting that the er stress coping mechanism counters the stresses intrinsic to embryos .
mammalian early embryos placed in vitro are vulnerable to a variety of physicochemical stresses such as shearing , temperature changes , altered ph , and higher oxygen pressure , all of which are known inducers of er stress coping responses .
these stresses alter gene expression , epigenetic mechanisms , and metabolism , reducing the embryonic development and viability .
although the influence of er stress coping responses on cellular physiology in adult tissues has been widely studied , their effects on the oocytes and early embryos of mammals remains unclear .
in a porcine model , the functional abundance of sxbp1 is low in mature oocytes and at the 1- , 2- , and 8-cell stages of embryos , but it is highly abundant at the germinal vesicle , 4-cell , morula , and blastocyst stages . in mouse cumulus - oocyte complexes , fatty acid - induced er stress impairs protein secretion , mitochondrial membrane potential , and embryo development .
er stress is a key mechanism mediating the developmental potential of oocytes . in mouse oocytes ,
the cancer drug doxorubicin affects the mitochondria , perk , and er - associated caspase-12 , while it inactivates parp , resulting in the activation of apoptotic signals .
this suggests that activation of er stress coping responses may contribute , at least in part , to ovarian failure in women treated for cancer . in mouse preimplantation embryos , er stress - induced coping response molecules such as perk , ask1 , bip , chop , gadd34 , ire1 , atf4 , atf6 , and xbp1 are expressed . taking into account that perk , ire1 , and atf6 are the three major transducers of the upr , the expression of the major transducers of the upr suggests that preimplantation embryos use the upr coping response as one mechanism to deal with preimplantation stress . in mice lacking upr - associated genes such as grp78 and ppp1r15a / ppp1r15b
, the embryos do not survive beyond preimplantation development , suggesting the indispensable role of these er chaperones and er stress - induced coping responses in preimplantation embryos .
xbp1 is an important transcription factor and regulator of a subset of genes activated during er stress - induced upr . in drosophila , xenopus , and mice , xbp1 is essential for early embryonic development . in mice ,
functional sxbp1 is abundant in the germinal vesicle of immature oocytes and on spindles in mii oocytes but is solely detected in the cytoplasm at the one - cell stage when sxbp1 mrna is scarce .
this indicates that sxbp1 acts as an important regulator of er stress - induced coping responses during specific developmental stages from oocyte to blastocyst . in mouse embryos ,
upr inducers such as tunicamycin and sorbitol increased nuclear sxbp1 at the one- and two - cell stages and activate xbp1 
 mrna splicing at the 8-cell , morula , and blastocyst stages , indicating that the ire arm of the upr is activated as an important coping response and adaptation to er stress in preimplantation embryos . in early mouse embryos ,
grp78/bip ( hspa5 ) , a central regulator for the er stress - induced upr coping response , is essential for cell proliferation and protecting the inner cell mass from apoptosis . considering the importance of stress - activated protein kinase mitogen - activated protein kinase kinase ( sapk - map3k ) activation during cellular stress and the early stage of er stress , as well as the indispensable role of stress - activated proteins and map3k for preimplantation embryonic development ,
er stress manifested by sapk - map3k is a normal event critical during preimplantation development .
the coupling of autophagy and upr has been implicated in a variety of biological processes .
induction of autophagy promotes preattachment development of in vitro - produced bovine embryos by reducing er stress , suggesting that autophagy / er stress balance is important for the developmental competence of early embryos .
the inhibition of er stress - induced upr responses by tudca was found to enhance the maturation and developmental potential of porcine oocytes by preventing er stress - mediated apoptosis in vitro . in mouse cumulus - oocyte complexes , fatty acid - induced er stress
coping responses are normalized by the upr inhibitor salubrinal , demonstrating that er stress is a key mechanism affecting oocyte developmental potential .
preimplantation embryos , under in vitro conditions , experience an increase in reactive oxygen species ( ros ) , oxidative stress , heat - shock stress , and/or the culture stress due to insufficiency of maternally - derived embryotropic factors .
growth factors and ros scavengers have been successfully used as a medium supplement in assisted reproductive technology ( art ) programs to prevent poor outcomes for embryo survival under in vitro conditions .
tudca attenuates xbp1 mrna splicing in embryos at the two - cell stage and abolishes dna fragmentation induced by tunicamycin or sorbitol in blastocysts and recovered nuclear localization of the sxbp1 protein .
in addition , tudca inhibits hyperosmolar - induced er stress coping responses as well as the er stress - induced apoptotic coping response during preimplantation embryo development .
er stress - induced coping responses may also play a critical role for embryo development after implantation . indeed , increased er stress in decidual tissue in pregnancy has been shown to be implicated in fetal growth restriction with and without pre - eclampsia .
sustained er stress acts as a cofactor of oxidative stress in decidual cells from patients with early pregnancy loss .
in decidual cells , excessive oxidative stress influences upr pathways to activate erad by decreasing valosin - containing protein , which is a type ii er - associated protein and a member of the aaaatpase family that facilitates delivery of misfolded proteins to the proteasome , which results in cell damage , inhibition of cell growth , and activation of apoptosis . among upr constituents , p - eif2 , grp94 , and
c / ebp homologous protein ( chop ) are increased in the placenta from intrauterine growth restriction and pre - eclampsia , indicating that er stress responses are also inducible under diseased conditions .
inositol - requiring enzyme 1 ( ire1 ) or xbp1 null mice are unable to produce functional placentas , which is lethal to the embryo , indicating that the ire1 arm of the upr coping response is essential for placental development and embryonic viability . in mice ,
cadmium - induced teratogenicity is associated with ros - mediated induction of er stress coping responses in the placenta .
maternal exposure to cadmium resulted in activation of perk , phosphorylation of placental eif2 , and an increase in chop , indicating that upr signaling is activated in the placenta due to cadmium - induced toxicity .
this further supports the notion that er stress - induced coping responses are important mechanisms in embryos and extraembryonic tissues following exposure to environmental toxins .
furthermore , er stress - induced coping responses in the maternal decidua and placenta may counteract developmental problems during implantation and postimplantation development .
stress coping mechanisms are critical to minimizing or overcoming damage caused by ever changing environmental conditions .
the upr pathway is mobilized in response to the accumulation of unfolded proteins and to ultimately regain er homeostasis .
various arms of the upr , an er stress coping response , are expressed in oocytes and preimplantation embryos , suggesting that er stress as a normal physiological adaptive / coping mechanism plays a pivotal role in the development of preimplantation embryos . as such , upr - associated molecules and pathways such as sxbp1 mrna may become useful markers for the potential diagnosis of stress conditions for preimplantation embryos .
most importantly , upr inhibitors , such as tudca , were found to effectively support the in vitro development of preimplantation embryos under stress conditions .
further identification of er stress - induced coping responses in preimplantation embryos would be helpful for a comprehensive understanding of development from preimplantation through early postimplantation .
 stress coping mechanisms are critical to minimize or overcome damage caused by ever changing environmental conditions . 
 they are designed to promote cell survival . the unfolded protein response ( upr ) pathway is mobilized in response to the accumulation of unfolded proteins , ultimately in order to regain endoplasmic reticulum ( er ) homeostasis . 
 various elements of coping responses to er stress including perk , ask1 , bip , chop , gadd34 , ire1 , atf4 , atf6 , and xbp1 have been identified and were found to be inducible in oocytes and preimplantation embryos , suggesting that , as a normal part of the cellular adaptive mechanism , these coping responses , including the upr , play a pivotal role in the development of preimplantation embryos . as such 
 , the upr - associated molecules and pathways may become useful markers for the potential diagnosis of stress conditions for preimplantation embryos . 
 after implantation , er stress - induced coping responses become physiologically important for a normal decidual response , placentation , and early organogenesis . 
 attenuation of er stress coping responses by tauroursodeoxycholate and salubrinal was effective for prevention of cell death of cultured embryos . 
 further elucidation of new and relevant er stress coping responses in periimplantation embryos might contribute to a comprehensive understanding of the regulation of normal development of embryonic development and potentiation of embryonic development in vitro . 