Ubiquitous expression of Akt1 p.(E17K) results in vascular defects and embryonic lethality in mice
| Autor: | Xuefei Ma, Nathaniel Laughner, Marjorie J. Lindhurst, Wenling Li, Leslie G. Biesecker, Jasmine Shwetar, Yoh-suke Mukouyama, Hannah C. Kondolf |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cell type animal structures Endothelium Angiogenesis Offspring AKT1 Mice Transgenic Biology Mural cell Proteus Syndrome Andrology 03 medical and health sciences Mice 0302 clinical medicine Genetics medicine Animals Molecular Biology Genetics (clinical) Peripheral Vascular Diseases Neovascularization Pathologic Wild type General Medicine Embryo Mammalian Embryonic stem cell 030104 developmental biology medicine.anatomical_structure embryonic structures Embryo Loss Female General Article Proto-Oncogene Proteins c-akt 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Hum Mol Genet |
| Popis: | Proteus syndrome is a progressive overgrowth disorder with vascular malformations caused by mosaic expression of the AKT1 c.49G > A, 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 (βA-Akt1WT/flx) was viable. Fewer than expected numbers of βA-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 βA-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 βA-Akt1WT/flx embryos, the capillary network failed to remodel. Mural cell coverage of the blood vessels was also reduced in βA-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 βA-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. |
| Databáze: | OpenAIRE |
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