{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T20:24:19Z","timestamp":1790627059365,"version":"4.1.0"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"20","funder":[{"name":"Intramural Research Program"},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["HG200328"],"award-info":[{"award-number":["HG200328"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["HG200388"],"award-info":[{"award-number":["HG200388"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,12,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Proteus syndrome is a progressive overgrowth disorder with vascular malformations caused by mosaic expression of the AKT1 c.49G\u2009&amp;gt;\u2009A, p.(E17K) activating variant which was predicted to cause lethality if expressed ubiquitously. To test that hypothesis, we used the ACTB-Cre gene to activate a conditional Akt1 p.(E17K) allele in the mouse. No offspring that was heterozygous for both Cre and the conditional allele (\u03b2A-Akt1WT\/flx) was viable. Fewer than expected numbers of \u03b2A-Akt1WT\/flx embryos were seen beginning at E11.5, but a few survived until E17.5. The phenotype ranged from mild to severe, but generally \u03b2A-Akt1WT\/flx embryos had fewer visible blood vessels and more hemorrhages than their wild-type littermates, which was suggestive of a vascular abnormality. Examination of E13.5 limb skin showed a primitive capillary network with increased branching complexity and abnormal patterning compared with wild-type skin. By E15.5, wild-type skin had undergone angiogenesis and formed a hierarchical network of remodeled vessels, whereas in \u03b2A-Akt1WT\/flx embryos, the capillary network failed to remodel. Mural cell coverage of the blood vessels was also reduced in \u03b2A-Akt1WT\/flx skin compared with that of wild type. Restricting expression of Akt1E17K to endothelial, cardiac or smooth muscle cells resulted in viable offspring and remodeled vasculature and did not recapitulate the \u03b2A-Akt1WT\/flx phenotype. We conclude that ubiquitous expression of Akt1E17K suppresses remodeling and inhibits the formation of a normal skin vasculature. We postulate that this failure prevents proper circulation necessary to support the growing embryo and that it is the result of interactions of multiple cell types with increased AKT signaling.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa216","type":"journal-article","created":{"date-parts":[[2020,10,7]],"date-time":"2020-10-07T11:43:30Z","timestamp":1602071010000},"page":"3350-3360","source":"Crossref","is-referenced-by-count":4,"title":["Ubiquitous expression of <i>Akt1<\/i> p.(E17K) results in vascular defects and embryonic lethality in mice"],"prefix":"10.1093","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8816-9879","authenticated-orcid":false,"given":"Marjorie J","family":"Lindhurst","sequence":"first","affiliation":[{"name":"Molecular Genomics and Metabolic Genetics Branch, NHGRI, NIH, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenling","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cell and Neuro-Vascular Biology, NHLBI, NIH, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel","family":"Laughner","sequence":"additional","affiliation":[{"name":"Molecular Genomics and Metabolic Genetics Branch, NHGRI, NIH, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmine J","family":"Shwetar","sequence":"additional","affiliation":[{"name":"Molecular Genomics and Metabolic Genetics Branch, NHGRI, NIH, Bethesda, MD 20892, USA"},{"name":"Department of Medicine, New York University, New York, NY 10010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah C","family":"Kondolf","sequence":"additional","affiliation":[{"name":"Molecular Genomics and Metabolic Genetics Branch, NHGRI, NIH, Bethesda, MD 20892, USA"},{"name":"Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefei","family":"Ma","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Cardiology, NHLBI, NIH, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoh-suke","family":"Mukouyama","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cell and Neuro-Vascular Biology, NHLBI, NIH, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie G","family":"Biesecker","sequence":"additional","affiliation":[{"name":"Molecular Genomics and Metabolic Genetics Branch, NHGRI, NIH, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,10,8]]},"reference":[{"key":"2021020911155969900_ref1","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1038\/sj.ejhg.5201638","article-title":"The challenges of Proteus syndrome: diagnosis and management","volume":"14","author":"Biesecker","year":"2006","journal-title":"Eur. 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