title: Extraembryonic but not embryonic SUMO-specific protease 2 is required for heart development.
abstract: SUMO-specific protease 2 (SENP2) activities to remove SUMO from its substrates is essential for development of trophoblast stem cells, niches and lineages. Global deletion of SENP2 leads to midgestation lethality, and causes severe defects in the placenta which is accompanied by embryonic brain and heart abnormalities. Because of the placental deficiencies, the role of SENP2 in development of the embryonic tissues has not been properly determined. The brain and heart abnormalities may be secondary to placental insufficiency. Here we have created a new mouse strain permitting conditional inactivation of SENP2. Mice homozygous for germline deletion of the conditional allele exhibit trophoblast defects and embryonic abnormalities resembling the global SENP2 knockout. However, tissue-specific disruptions of SENP2 demonstrate its dispensable role in embryogenesis. Placental expression of SENP2 is necessary and sufficient for embryonic heart and brain development. Using a protease deficient model, we further demonstrate the requirement of SENP2-dependent SUMO modification in development of all major trophoblast lineages. SENP2 regulates sumoylation of Mdm2 which controls p53 activities critical for G-S transition of mitotic division and endoreduplication in trophoblast proliferation and differentiation, respectively. The differentiation of trophoblasts is also dependent on SENP2-mediated activation of p57(Kip2), a CDK-specific inhibitor required for endoreduplication.
authors.affiliation: Department of Biomedical Genetics, Center for Oral Biology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 611, Rochester, NY 14642.
authors.forename: Eri O
authors.initials: EO
authors.lastname: Maruyama
authors.affiliation: Department of Biomedical Genetics, Center for Oral Biology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 611, Rochester, NY 14642.
authors.forename: Heng
authors.initials: H
authors.lastname: Lin
authors.affiliation: Department of Biomedical Genetics, Center for Oral Biology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 611, Rochester, NY 14642.
authors.forename: Shang-Yi
authors.initials: SY
authors.lastname: Chiu
authors.affiliation: Department of Biomedical Genetics, Center for Oral Biology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 611, Rochester, NY 14642.
authors.forename: H-M Ivy
authors.initials: HM
authors.lastname: Yu
authors.affiliation: Departments of Pediatrics, Pharmacology and Physiology, and Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Box 631, Rochester, NY 14642.
authors.forename: George A
authors.initials: GA
authors.lastname: Porter
authors.affiliation: Department of Biomedical Genetics, Center for Oral Biology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 611, Rochester, NY 14642.|Stem Cell and Regenerative Medicine Institute, University of Rochester Medical Center, 601 Elmwood Avenue, Box 611, Rochester, NY 14642.|Wilmot Cancer Institute, University of Rochester Medical Center, 601 Elmwood Avenue, Box 611, Rochester, NY 14642.
authors.forename: Wei
authors.initials: W
authors.lastname: Hsu
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D055786:Gene Knockout Techniques; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006720:Homozygote; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D038081:Organogenesis / Q000235:genetics*; D010920:Placenta / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D011247:Pregnancy; D021381:Protein Transport; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D058207:Sumoylation; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism
chemical_list: D050761:Cyclin-Dependent Kinase Inhibitor p57; D051736:Proto-Oncogene Proteins c-mdm2; D003546:Cysteine Endopeptidases; C439066:Senp2 protein, mouse