title: The A-kinase Anchoring Protein GSKIP Regulates GSK3β Activity and Controls Palatal Shelf Fusion in Mice.
abstract: A-kinase anchoring proteins (AKAPs) represent a family of structurally diverse proteins, all of which bind PKA. A member of this family is glycogen synthase kinase 3β (GSK3β) interaction protein (GSKIP). GSKIP interacts with PKA and also directly interacts with GSK3β. The physiological function of the GSKIP protein in vivo is unknown. We developed and characterized a conditional knock-out mouse model and found that GSKIP deficiency caused lethality at birth. Embryos obtained through Caesarean section at embryonic day 18.5 were cyanotic, suffered from respiratory distress, and failed to initiate breathing properly. Additionally, all GSKIP-deficient embryos showed an incomplete closure of the palatal shelves accompanied by a delay in ossification along the fusion area of secondary palatal bones. On the molecular level, GSKIP deficiency resulted in decreased phosphorylation of GSK3β at Ser-9 starting early in development (embryonic day 10.5), leading to enhanced GSK3β activity. At embryonic day 18.5, GSK3β activity decreased to levels close to that of wild type. Our findings reveal a novel, crucial role for GSKIP in the coordination of GSK3β signaling in palatal shelf fusion.
authors.affiliation: From the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Strasse 10, 13125 Berlin.
authors.forename: Veronika Anita
authors.initials: VA
authors.lastname: Deák
authors.affiliation: From the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Strasse 10, 13125 Berlin.
authors.forename: Philipp
authors.initials: P
authors.lastname: Skroblin
authors.affiliation: the Institute of Anatomy, Charité University Medicine, Philippstrasse 12, 10115 Berlin, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Dittmayer
authors.affiliation: the Institute for Neuropathology, University of Freiburg, Breisacher Strasse 64, 79106 Freiburg, and.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Knobeloch
authors.affiliation: the Institute of Anatomy, Charité University Medicine, Philippstrasse 12, 10115 Berlin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bachmann
authors.affiliation: From the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Strasse 10, 13125 Berlin, the DZHK (German Centre for Cardiovascular Research), partner site Berlin, Oudenarder Strasse 16, 13347 Berlin, Germany enno.klussmann@mdc-berlin.de.
authors.forename: Enno
authors.identifier: http://orcid.org/0000-0003-4004-5003
authors.initials: E
authors.lastname: Klussmann
mesh_terms: D000483:Alleles; D000818:Animals; D002972:Cleft Palate / Q000196:embryology / Q000201:enzymology / Q000473:pathology; D020964:Embryo Loss / Q000378:metabolism; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000196:embryology / Q000201:enzymology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D057898:Hemizygote; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010159:Palate / Q000002:abnormalities / Q000196:embryology* / Q000201:enzymology / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000172:deficiency / Q000378:metabolism*; D012119:Respiration
chemical_list: C000607629:GSKIP protein, mouse; D012333:RNA, Messenger; D012097:Repressor Proteins; D010768:Phosphoserine; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: A-kinase anchoring protein (AKAP); GSK3β interaction protein; animal model; cell signaling; cleft palate; cyclic AMP (cAMP); development; glycogen synthase kinase 3 (GSK-3); protein kinase A (PKA)