title: Sox7 and Sox17 are strain-specific modifiers of the lymphangiogenic defects caused by Sox18 dysfunction in mice.
abstract: Developmental defects caused by targeted gene inactivation in mice are commonly subject to strain-specific modifiers that modulate the severity of the phenotype. Although several genetic modifier loci have been mapped in mice, the gene(s) residing at these loci are mostly unidentified, and the molecular mechanisms of modifier action remain poorly understood. Mutations in Sox18 cause a variable phenotype in the human congenital syndrome hypotrichosis-lymphedema-telangiectasia, and the phenotype of Sox18-null mice varies from essentially normal to completely devoid of lymphatic vasculature and lethal, depending on the strain of the mice, suggesting a crucial role for strain-specific modifiers in this system. Here we show that two closely related Group F Sox factors, SOX7 and SOX17, are able to functionally substitute for SOX18 in vitro and in vivo. SOX7 and SOX17 are not normally expressed during lymphatic development, excluding a conventional redundancy mechanism. Instead, these genes are activated specifically in the absence of SOX18 function, and only in certain strains. Our studies identify Sox7 and Sox17 as modifiers of the Sox18 mutant phenotype, and reveal their mechanism of action as a novel mode of strain-specific compensatory upregulation.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld 4072, Australia.
authors.forename: Brett
authors.initials: B
authors.lastname: Hosking
authors.forename: Mathias
authors.initials: M
authors.lastname: François
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wilhelm
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Orsenigo
authors.forename: Andrea
authors.initials: A
authors.lastname: Caprini
authors.forename: Terje
authors.initials: T
authors.lastname: Svingen
authors.forename: Desmond
authors.initials: D
authors.lastname: Tutt
authors.forename: Tara
authors.initials: T
authors.lastname: Davidson
authors.forename: Catherine
authors.initials: C
authors.lastname: Browne
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Dejana
authors.forename: Peter
authors.initials: P
authors.lastname: Koopman
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D024002:HMGB Proteins / Q000235:genetics / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007039:Hypotrichosis / Q000235:genetics; D042583:Lymphangiogenesis / Q000235:genetics / Q000502:physiology*; D008209:Lymphedema / Q000235:genetics; D051379:Mice; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055760:SOXF Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013045:Species Specificity; D013577:Syndrome; D013684:Telangiectasis / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D015854:Up-Regulation; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D017931:DNA Primers; D024002:HMGB Proteins; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D055760:SOXF Transcription Factors; C511606:Sox17 protein, mouse; C490653:Sox18 protein, mouse; C102515:Sox7 protein, mouse; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein