title: Sox7, Sox17, and Sox18 Cooperatively Regulate Vascular Development in the Mouse Retina.
abstract: Vascular development and maintenance are controlled by a complex transcriptional program, which integrates both extracellular and intracellular signals in endothelial cells. Here we study the roles of three closely related SoxF family transcription factors-Sox7, Sox17, and Sox18 -in the developing and mature mouse vasculature using targeted gene deletion on a mixed C57/129/CD1 genetic background. In the retinal vasculature, each SoxF gene exhibits a distinctive pattern of expression in different classes of blood vessels. On a mixed genetic background, vascular endothelial-specific deletion of individual SoxF genes has little or no effect on vascular architecture or differentiation, a result that can be explained by overlapping function and by reciprocal regulation of gene expression between Sox7 and Sox17. By contrast, combined deletion of Sox7, Sox17, and Sox18 at the onset of retinal angiogenesis leads to a dense capillary plexus with a nearly complete loss of radial arteries and veins, whereas the presence of a single Sox17 allele largely restores arterial identity, as determined by vascular smooth muscle cell coverage. In the developing retina, expression of all three SoxF genes is reduced in the absence of Norrin/Frizzled4-mediated canonical Wnt signaling, but SoxF gene expression is unaffected by reduced VEGF signaling in response to deletion of Neuropilin1 (Npn1). In adulthood, Sox7, Sox17, and Sox18 act in a largely redundant manner to maintain blood vessel function, as adult onset vascular endothelial-specific deletion of all three SoxF genes leads to massive edema despite nearly normal vascular architecture. These data reveal critical and partially redundant roles for Sox7, Sox17 and Sox18 in vascular growth, differentiation, and maintenance.
authors.affiliation: Departments of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, United States of America.
authors.forename: Yulian
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Departments of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, United States of America.|Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Williams
authors.affiliation: Departments of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, United States of America.|Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, United States of America.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Smallwood
authors.affiliation: Departments of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, United States of America.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, United States of America.|Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, United States of America.|Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, United States of America.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Nathans
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D024002:HMGB Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D005810:Multigene Family; D018919:Neovascularization, Physiologic / Q000235:genetics; D010211:Papilledema / Q000209:etiology / Q000235:genetics / Q000473:pathology; D051880:Receptors, Notch / Q000378:metabolism; D012171:Retinal Vessels / Q000254:growth & development* / Q000378:metabolism*; D055760:SOXF Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D024002:HMGB Proteins; D051880:Receptors, Notch; D055760:SOXF Transcription Factors; C511606:Sox17 protein, mouse; C490653:Sox18 protein, mouse; C102515:Sox7 protein, mouse