title: cAMP-responsive element binding protein: a vital link in embryonic hormonal adaptation.
abstract: The transcription factor cAMP responsive element-binding protein (CREB) and activating transcription factors (ATFs) are downstream components of the insulin/IGF cascade, playing crucial roles in maintaining cell viability and embryo survival. One of the CREB target genes is adiponectin, which acts synergistically with insulin. We have studied the CREB-ATF-adiponectin network in rabbit preimplantation development in vivo and in vitro. From the blastocyst stage onwards, CREB and ATF1, ATF3, and ATF4 are present with increasing expression for CREB, ATF1, and ATF3 during gastrulation and with a dominant expression in the embryoblast (EB). In vitro stimulation with insulin and IGF-I reduced CREB and ATF1 transcripts by approximately 50%, whereas CREB phosphorylation was increased. Activation of CREB was accompanied by subsequent reduction in adiponectin and adiponectin receptor (adipoR)1 expression. Under in vivo conditions of diabetes type 1, maternal adiponectin levels were up-regulated in serum and endometrium. Embryonic CREB expression was altered in a cell lineage-specific pattern. Although in EB cells CREB localization did not change, it was translocated from the nucleus into the cytosol in trophoblast (TB) cells. In TB, adiponectin expression was increased (diabetic 427.8 ± 59.3 pg/mL vs normoinsulinaemic 143.9 ± 26.5 pg/mL), whereas it was no longer measureable in the EB. Analysis of embryonic adipoRs showed an increased expression of adipoR1 and no changes in adipoR2 transcription. We conclude that the transcription factors CREB and ATFs vitally participate in embryo-maternal cross talk before implantation in a cell lineage-specific manner. Embryonic CREB/ATFs act as insulin/IGF sensors. Lack of insulin is compensated by a CREB-mediated adiponectin expression, which may maintain glucose uptake in blastocysts grown in diabetic mothers.
authors.affiliation: Department of Anatomy and Cell Biology, Martin Luther University Faculty of Medicine, Grosse Steinstrasse 52, D-06097 Halle (Saale), Germany. maria.schindler@medizin.uni-halle.de
authors.forename: Maria
authors.initials: M
authors.lastname: Schindler
authors.forename: Sünje
authors.initials: S
authors.lastname: Fischer
authors.forename: René
authors.initials: R
authors.lastname: Thieme
authors.forename: Bernd
authors.initials: B
authors.lastname: Fischer
authors.forename: Anne Navarrete
authors.initials: AN
authors.lastname: Santos
mesh_terms: D051697:Activating Transcription Factor 1 / Q000235:genetics* / Q000378:metabolism; D051700:Activating Transcription Factor 3 / Q000235:genetics* / Q000378:metabolism; D052242:Adiponectin / Q000235:genetics / Q000378:metabolism; D000496:Alloxan; D000818:Animals; D001755:Blastocyst / Q000187:drug effects / Q000378:metabolism*; D015153:Blotting, Western; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D005260:Female; D054262:Gastrulation / Q000187:drug effects / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D011817:Rabbits; D054419:Receptors, Adiponectin / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014327:Trophoblasts / Q000187:drug effects / Q000378:metabolism
chemical_list: D051697:Activating Transcription Factor 1; D051700:Activating Transcription Factor 3; D052242:Adiponectin; D017362:Cyclic AMP Response Element-Binding Protein; D007328:Insulin; D054419:Receptors, Adiponectin; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D000496:Alloxan