{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T23:23:10Z","timestamp":1788909790226,"version":"build-2803163510"},"reference-count":47,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,6,24]],"date-time":"2023-06-24T00:00:00Z","timestamp":1687564800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"IZKF Jena Advanced Medical Scientist program","award":["AMSP06"],"award-info":[{"award-number":["AMSP06"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The mitogen-activated protein kinase organizer 1 (MORG1) is a scaffold molecule for the ERK signaling pathway, but also binds to prolyl-hydroxylase 3 and modulates HIF\u03b1 expression. To obtain further insight into the role of MORG1, knockout-mice were generated by homologous recombination. While Morg1+\/\u2212 mice developed normally without any apparent phenotype, there were no live-born Morg1\u2212\/\u2212 knockout offspring, indicating embryonic lethality. The intrauterine death of Morg1\u2212\/\u2212 embryos is caused by a severe failure to develop brain and other neuronal structures such as the spinal cord and a failure of chorioallantoic fusion. On E8.5, Morg1\u2212\/\u2212 embryos showed severe underdevelopment and proliferative arrest as indicated by absence of Ki67 expression, impaired placental vascularization and altered phenotype of trophoblast giant cells. On E9.5, the malformed Morg1\u2212\/\u2212 embryos showed defective turning into the final fetal position and widespread apoptosis in many structures. In the subsequent days, apoptosis and decomposition of embryonic tissue progressed, accompanied by a massive infiltration of inflammatory cells. Developmental aberrancies were accompanied by altered expression of HIF-1\/2\u03b1 and VEGF-A and caspase-3 activation in embryos and extraembryonic tissues. In conclusion, the results suggest a multifactorial process that causes embryonic death in homozygous Morg1 mutant mice, described here, to the best of our knowledge, for the first time.<\/jats:p>","DOI":"10.3390\/biom13071037","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T01:42:32Z","timestamp":1687743752000},"page":"1037","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Targeted Disruption of the MORG1 Gene in Mice Causes Embryonic Resorption in Early Phase of Development"],"prefix":"10.3390","volume":"13","author":[{"given":"Sophie","family":"Wulf","sequence":"first","affiliation":[{"name":"Department of Internal Medicine III, Jena University Hospital, 07747 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Mizko","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, Jena University Hospital, 07747 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0757-3525","authenticated-orcid":false,"given":"Karl-Heinz","family":"Herrmann","sequence":"additional","affiliation":[{"name":"Medical Physics Group, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, 07747 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4720-8688","authenticated-orcid":false,"given":"Marta","family":"S\u00e1nchez-Carbonell","sequence":"additional","affiliation":[{"name":"Department of Neurology, Jena University Hospital, 07747 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9321-829X","authenticated-orcid":false,"given":"Anja","family":"Urbach","sequence":"additional","affiliation":[{"name":"Department of Neurology, Jena University Hospital, 07747 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelius","family":"Lemke","sequence":"additional","affiliation":[{"name":"Institute for Anatomy I, Jena University Hospital, 07743 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Berndt","sequence":"additional","affiliation":[{"name":"Institute of Forensic Medicine, Section Pathology, Jena University Hospital, 07743 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4982-5647","authenticated-orcid":false,"given":"Ivonne","family":"Loeffler","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, Jena University Hospital, 07747 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3291-0610","authenticated-orcid":false,"given":"Gunter","family":"Wolf","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, Jena University Hospital, 07747 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1007\/s13238-011-1018-1","article-title":"Structure and function of WD40 domain proteins","volume":"2","author":"Xu","year":"2011","journal-title":"Protein Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6981","DOI":"10.1073\/pnas.0305894101","article-title":"Modular construction of a signaling scaffold: MORG1 interacts with components of the ERK cascade and links ERK signaling to specific agonists","volume":"101","author":"Vomastek","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1083\/jcb.200607025","article-title":"p14-MP1-MEK1 signaling regulates endosomal traffic and cellular proliferation during tissue homeostasis","volume":"175","author":"Teis","year":"2006","journal-title":"J. Cell Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1080\/17460441.2019.1613370","article-title":"The transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy","volume":"14","author":"Albadari","year":"2019","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s12276-019-0299-y","article-title":"Hypoxia signaling in human diseases and therapeutic targets","volume":"51","author":"Lee","year":"2019","journal-title":"Exp. Mol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"F511","DOI":"10.1152\/ajprenal.00236.2014","article-title":"Morg1 heterozygous deficiency ameliorates hypoxia-induced acute renal injury","volume":"308","author":"Loeffler","year":"2015","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"8645","DOI":"10.1074\/jbc.M513751200","article-title":"The novel WD-repeat protein Morg1 acts as a molecular scaffold for hypoxia-inducible factor prolyl hydroxylase 3 (PHD3)","volume":"281","author":"Hopfer","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1083\/jcb.201208150","article-title":"The WD40 protein Morg1 facilitates Par6-aPKC binding to Crb3 for apical identity in epithelial cells","volume":"200","author":"Hayase","year":"2013","journal-title":"J. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.coisb.2017.03.005","article-title":"Mechanisms of Cell Polarization","volume":"3","author":"Rappel","year":"2017","journal-title":"Curr. Opin. Syst. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Choi, S. (2018). Encyclopedia of Signaling Molecules, Springer International Publishing.","DOI":"10.1007\/978-3-319-67199-4"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"F1273","DOI":"10.1152\/ajprenal.00204.2009","article-title":"Morg1 heterozygous mice are protected from acute renal ischemia-reperfusion injury","volume":"297","author":"Hammerschmidt","year":"2009","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2017","DOI":"10.1093\/ndt\/gfx202","article-title":"Heterozygosity of mitogen-activated protein kinase organizer 1 ameliorates diabetic nephropathy and suppresses epithelial-to-mesenchymal transition-like changes in db\/db mice","volume":"32","author":"Loeffler","year":"2017","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Jankowski, E., Wulf, S., Ziller, N., Wolf, G., and Loeffler, I. (2021). MORG1-A Negative Modulator of Renal Lipid Metabolism in Murine Diabetes. Biomedicines, 10.","DOI":"10.3390\/biomedicines10010030"},{"key":"ref_14","unstructured":"Herrmann, K.H., Hung, L.Y., and Reichenbach, J.R. (2022, January 7\u201312). Fast 3D Isotropic High-Resolution MRI of Mouse Brain Using a Variable Flip Angle RARE Sequence with T2 Compensation @9. 4T. Proceedings of the 30th Annual Meeting ISMRM, London, UK."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/s00412-018-0659-8","article-title":"Ki-67: More than a proliferation marker","volume":"127","author":"Sun","year":"2018","journal-title":"Chromosoma"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1007\/978-1-4939-4023-3_3","article-title":"The Role of WT1 in Embryonic Development and Normal Organ Homeostasis","volume":"1467","author":"Wilm","year":"2016","journal-title":"Methods Mol. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1126\/science.2660260","article-title":"Altering the genome by homologous recombination","volume":"244","author":"Capecchi","year":"1989","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/978-1-60761-974-1_12","article-title":"Generating conditional knockout mice","volume":"693","author":"Friedel","year":"2011","journal-title":"Methods Mol. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/nature26002","article-title":"Placentation defects are highly prevalent in embryonic lethal mouse mutants","volume":"555","author":"Fineberg","year":"2018","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1177\/0300985810395725","article-title":"Early embryonic lethality in genetically engineered mice: Diagnosis and phenotypic analysis","volume":"49","author":"Papaioannou","year":"2012","journal-title":"Vet. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6445","DOI":"10.1128\/MCB.24.14.6445-6455.2004","article-title":"Chorioallantoic fusion defects and embryonic lethality resulting from disruption of Zfp36L1, a gene encoding a CCCH tandem zinc finger protein of the Tristetraprolin family","volume":"24","author":"Stumpo","year":"2004","journal-title":"Mol. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1128\/MCB.26.1.77-87.2006","article-title":"Defects in yolk sac vasculogenesis, chorioallantoic fusion, and embryonic axis elongation in mice with targeted disruption of Yap65","volume":"26","author":"Boone","year":"2006","journal-title":"Mol. Cell Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"E935","DOI":"10.1152\/ajpendo.00319.2014","article-title":"The SK3 channel promotes placental vascularization by enhancing secretion of angiogenic factors","volume":"307","author":"Rada","year":"2014","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/s41576-019-0169-4","article-title":"Mechanisms of early placental development in mouse and humans","volume":"21","author":"Hemberger","year":"2020","journal-title":"Nat. Rev. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1111\/dgd.12030","article-title":"Apicobasal polarity and neural tube closure","volume":"55","author":"Eom","year":"2013","journal-title":"Dev. Growth Differ."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2544","DOI":"10.1038\/sj.onc.1204363","article-title":"A targeted mouse Brca1 mutation removing the last BRCT repeat results in apoptosis and embryonic lethality at the headfold stage","volume":"20","author":"Hohenstein","year":"2001","journal-title":"Oncogene"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2060","DOI":"10.1111\/j.1432-1033.2004.04132.x","article-title":"Oxidative neuronal injury. The dark side of ERK1\/2","volume":"271","author":"Chu","year":"2004","journal-title":"Eur. J. Biochem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2715","DOI":"10.1096\/fj.01-0546fje","article-title":"Dissecting hypoxia-dependent and hypoxia-independent steps in the HIF-1alpha activation cascade: Implications for HIF-1alpha gene therapy","volume":"15","author":"Hofer","year":"2001","journal-title":"FASEB J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.cell.2006.12.021","article-title":"Trekking across the brain: The journey of neuronal migration","volume":"128","author":"Ayala","year":"2007","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1007\/s00109-007-0196-z","article-title":"Transcriptional regulation of neurogenesis: Potential mechanisms in cerebral ischemia","volume":"85","author":"Scholzke","year":"2007","journal-title":"J. Mol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1038\/sj.embor.embor939","article-title":"An essential function of the mitogen-activated protein kinase Erk2 in mouse trophoblast development","volume":"4","author":"Vella","year":"2003","journal-title":"EMBO Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/S0960-9822(99)80164-X","article-title":"Embryonic death of Mek1-deficient mice reveals a role for this kinase in angiogenesis in the labyrinthine region of the placenta","volume":"9","author":"Giroux","year":"1999","journal-title":"Curr. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3191","DOI":"10.1101\/gad.853700a","article-title":"Placental cell fates are regulated in vivo by HIF-mediated hypoxia responses","volume":"14","author":"Adelman","year":"2000","journal-title":"Genes Dev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1101\/gad.12.2.149","article-title":"Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha","volume":"12","author":"Iyer","year":"1998","journal-title":"Genes Dev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.modgep.2006.08.002","article-title":"Cloning of hif-1alpha and hif-2alpha and mRNA expression pattern during development in zebrafish","volume":"7","author":"Rojas","year":"2007","journal-title":"Gene Expr. Patterns"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"10479","DOI":"10.1128\/MCB.25.23.10479-10491.2005","article-title":"Hypoxia-inducible factors 1alpha and 2alpha regulate trophoblast differentiation","volume":"25","author":"Fryer","year":"2005","journal-title":"Mol. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1177\/1947601911423031","article-title":"Vascular Endothelial Growth Factor (VEGF) and Its Receptor (VEGFR) Signaling in Angiogenesis: A Crucial Target for Anti- and Pro-Angiogenic Therapies","volume":"2","author":"Shibuya","year":"2011","journal-title":"Genes Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1186\/gb-2005-6-2-209","article-title":"The vascular endothelial growth factor (VEGF) family: Angiogenic factors in health and disease","volume":"6","author":"Holmes","year":"2005","journal-title":"Genome Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.biocel.2016.06.001","article-title":"Dimer conformation of soluble PECAM-1, an endothelial marker","volume":"77","author":"Jiang","year":"2016","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1002\/bdra.10090","article-title":"Caspase-3 mediates retinoid-induced apoptosis in the organogenesis-stage mouse limb","volume":"67","author":"Hales","year":"2003","journal-title":"Birth Defects Res. A Clin. Mol. Teratol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"pdb-prot087312","DOI":"10.1101\/pdb.prot087312","article-title":"Detecting Cleaved Caspase-3 in Apoptotic Cells by Flow Cytometry","volume":"2016","author":"Crowley","year":"2016","journal-title":"Cold Spring Harb. Protoc."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Theiler, K. (1989). The House Mouse: Atlas of Embryonic Development, Springer.","DOI":"10.1007\/978-3-642-88418-4"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.neulet.2009.03.048","article-title":"Reduced Morg1 expression in ischemic human brain","volume":"455","author":"Haase","year":"2009","journal-title":"Neurosci. Lett."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.brainres.2012.09.017","article-title":"Morg1(+\/-) heterozygous mice are protected from experimentally induced focal cerebral ischemia","volume":"1482","author":"Stahr","year":"2012","journal-title":"Brain Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1038\/s41586-019-1469-8","article-title":"Molecular architecture of lineage allocation and tissue organization in early mouse embryo","volume":"572","author":"Peng","year":"2019","journal-title":"Nature"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1016\/j.devcel.2020.11.018","article-title":"Spatial Transcriptome for the Molecular Annotation of Lineage Fates and Cell Identity in Mid-gastrula Mouse Embryo","volume":"55","author":"Peng","year":"2020","journal-title":"Dev. Cell"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1038\/nprot.2017.003","article-title":"Spatial transcriptomic analysis of cryosectioned tissue samples with Geo-seq","volume":"12","author":"Chen","year":"2017","journal-title":"Nat. Protoc."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/7\/1037\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:59:51Z","timestamp":1760126391000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/7\/1037"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,24]]},"references-count":47,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["biom13071037"],"URL":"https:\/\/doi.org\/10.3390\/biom13071037","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,24]]}}}