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Targeted Disruption of the MORG1 Gene in Mice Causes Embryonic Resorption in Early Phase of Development

Affiliation
Department of Internal Medicine III, Jena University Hospital, 07747 Jena, Germany(G.W.)
Wulf, Sophie;
Affiliation
Department of Internal Medicine III, Jena University Hospital, 07747 Jena, Germany(G.W.)
Mizko, Luisa;
ORCID
0000-0003-0757-3525
Affiliation
Medical Physics Group, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, 07747 Jena, Germany;
Herrmann, Karl-Heinz;
ORCID
0000-0003-4720-8688
Affiliation
Department of Neurology, Jena University Hospital, 07747 Jena, Germany(A.U.)
Sánchez-Carbonell, Marta;
ORCID
0000-0002-9321-829X
Affiliation
Department of Neurology, Jena University Hospital, 07747 Jena, Germany(A.U.)
Urbach, Anja;
Affiliation
Institute for Anatomy I, Jena University Hospital, 07743 Jena, Germany;
Lemke, Cornelius;
Affiliation
Institute of Forensic Medicine, Section Pathology, Jena University Hospital, 07743 Jena, Germany;
Berndt, Alexander;
ORCID
0000-0003-4982-5647
Affiliation
Department of Internal Medicine III, Jena University Hospital, 07747 Jena, Germany(G.W.)
Loeffler, Ivonne;
ORCID
0000-0002-3291-0610
Affiliation
Department of Internal Medicine III, Jena University Hospital, 07747 Jena, Germany(G.W.)
Wolf, Gunter

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 HIFα expression. To obtain further insight into the role of MORG1, knockout-mice were generated by homologous recombination. While Morg1+/− mice developed normally without any apparent phenotype, there were no live-born Morg1−/− knockout offspring, indicating embryonic lethality. The intrauterine death of Morg1−/− 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−/− 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−/− 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-1/2α 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.

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