The phenogenetics of hair mutants in the house mouse: Opossum and Ragged

Mann, Stanley J.

doi:10.1017/s0016672300003372

Cited by 15 publications

(6 citation statements)

References 13 publications

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“…The RaOP heterozygotes resemble the homozygotes of the other three allelic forms and generally display a hairless and edematous phenotype (52,53). Therefore, we utilized the RaOP mouse model to investigate the in vivo effect of this mutant form of Sox18 on the expression levels of VCAM-1.…”

Section: Vcam-1 Expression In Lung Skeletal Muscle and Skin Is Signmentioning

confidence: 99%

The VCAM-1 Gene That Encodes the Vascular Cell Adhesion Molecule Is a Target of the Sry-related High Mobility Group Box Gene, Sox18

Hosking

Wang

Downes

et al. 2004

Journal of Biological Chemistry

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VCAM-1 (vascular cell adhesion molecule-1) and Sox18 are involved in vascular development. VCAM-1 is an important adhesion molecule that is expressed on endothelial cells and has a critical role in endothelial activation, inflammation, lymphatic pathophysiology, and atherogenesis. The Sry-related high mobility group box factor Sox18 has previously been implicated in endothelial pathologies. Mutations in human and mouse Sox18 leads to hypotrichosis and lymphedema. Furthermore, both Sox18 and VCAM-1 have very similar spatio-temporal patterns of expression, which is suggestive of crosstalk. We use biochemical techniques, cell culture systems, and the ragged opossum (RaOP) mouse model with a naturally occurring mutation in Sox18 to demonstrate that VCAM-1 is an important target of Sox18. Transfection, site-specific mutagenesis, and gel shift analyses demonstrated that Sox18 directly targeted and trans-activated VCAM-1 expression. Importantly, the naturally occurring Sox18 mutant attenuates the expression and activation of VCAM-1 in vitro. Furthermore, in vivo quantitation of VCAM-1 mRNA levels in wild type and RaOP mice demonstrates that RaOP animals show a dramatic and significant reduction in VCAM-1 mRNA expression in lung, skin, and skeletal muscle. Our observation that the VCAM-1 gene is an important target of SOX18 provides the first molecular insights into the vascular abnormalities in the mouse mutant ragged and the human hypotrichosislymphedema-telangiectasia disorder.

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Section: Vcam-1 Expression In Lung Skeletal Muscle and Skin Is Signmentioning

confidence: 99%

The VCAM-1 Gene That Encodes the Vascular Cell Adhesion Molecule Is a Target of the Sry-related High Mobility Group Box Gene, Sox18

Hosking

Wang

Downes

et al. 2004

Journal of Biological Chemistry

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“…Ra homozygotes, however, almost completely lack vibrissae and coat hairs, display generalized edema and cyanosis, and rarely survive past weaning (5). In a more severe Ra mutation, Ra Op , heterozygotes typically show a phenotype similar to that of Ra homozygotes, whereas Ra Op homozygotes die by 11.5 days postcoitus (dpc) (10,24). The coat defects in Ra mice are due to a reduction in the total number of hair follicles, with the later-forming follicles being the most affected (33).…”

Section: Siblings Sox18mentioning

confidence: 99%

Mice Null for Sox18 Are Viable and Display a Mild Coat Defect

Pennisi

Bowles

Nagy

et al. 2000

Molecular and Cellular Biology

111

102

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We have previously shown that Sox18 is expressed in developing vascular endothelium and hair follicles during mouse embryogenesis and that point mutations in Sox18 are the underlying cause of cardiovascular and hair follicle defects in ragged (Ra) mice. Here we describe the analysis of Sox18 ؊/؊ mice produced by gene targeting. Despite the profound defects seen in Ra mice, Sox18 ؊/؊ mice have no obvious cardiovascular defects and only a mild coat defect with a reduced proportion of zigzag hairs. A reduction in the amount of pheomelanin pigmentation in hair shafts was also observed; later-forming hair follicles showed a reduced subapical pheomelanin band, giving Sox18 ؊/؊ mice a slightly darker appearance than Sox18 ؉/؉ and Sox18siblings. Sox18 ؊/؊ mice are viable and fertile and show no difference in the ability to thrive relative to littermates. Because of the mild effect of the mutation on the phenotype of Sox18 ؊/؊ mice, we conclude that the semidominant nature of the Ra mutations is due to a trans-dominant negative effect mediated by the mutant SOX18 proteins rather than haploinsufficiency as has been observed for other SOX genes. Due to the similarity of SOX18 to other subgroup F SOX proteins, SOX7 and ؊17, and the overlap in expression of these genes, functional redundancy amongst these SOX proteins could also account for the mild phenotype of Sox18Members of the SOX (Sry-type HMG box) gene family encode transcription factors that have a wide range of roles in development (reviewed by Wegner [39]). SOX proteins bind DNA in a sequence-specific manner, and a heptameric SOX consensus binding motif, 5Ј-(A/T)(A/T)CAA(A/T)G-3Ј, has been identified (12). Most tissues and cell types express at least one SOX gene at one stage or another of their development (39). Moreover, many cell types or tissues express more than one SOX gene at certain times (6,20,22,36,37).Gene targeting experiments with the mouse have assigned vital roles in development to numerous SOX genes: Sox1 in lens formation (28), Sox4 in cardiac tract outflow formation and B-lymphocyte development (32), and Sox9 in chondrogenesis (3). This has been reinforced by mutations in human SOX genes: SRY mutations in sex reversal and gonadal dysgenesis (2,11,13,15), SOX9 mutations in the bone dysmorphogenesis and sex reversal syndrome campomelic dysplasia (9, 38), and SOX10 mutations in various neurocristopathies such as Waardenberg-Shah syndrome 4 (30) and the Yemenite deaf-blind hypopigmentation syndrome (4). Further, such mutations have revealed an importance of dosage for some SOX genes, with deletion or mutation of one allele of SOX9 or SOX10 resulting in a disease phenotype (9,30,38).We have previously shown that point mutations in Sox18 are the underlying cause of profound cardiovascular and hair follicle defects in ragged (Ra) mice (29). Ra heterozygotes have thin, ragged coats comprised of guard hairs but lacking the later-forming auchenes and zigzags (5). Ra homozygotes, however, almost completely lack vibrissae and coat hairs, display generalized e...

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“…In all three cases, heterozygotes are characterised by a thin, ragged coat and oedema at birth caused by vascular dysfunction, while homozygotes are virtually naked and usually die soon after birth (Carter and Phillips, 1954;Green and Mann, 1961;Mann, 1963;Slee, 1957a, b;Wallace, 1979). Ra op represents a more severely affected class of mutant, with heterozygotes resembling homozy-gotes of the other three alleles (Green and Mann, 1961;Mann, 1963). Homozygous Ra op animals have been reported to die in utero as early as 11 days postcoitum, likely due to cardiovascular dysfunction, while only an estimated 17% of Ra op heterozygotes are born and survive to weaning age (Green and Mann, 1961).…”

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confidence: 99%

“…1b,c). The deletion of a guanine residue at coding nucle- References: Carter and Phillips, 1954;Green and Mann, 1961;Mann, 1963;Slee 1957a,b;Wallace, 1979. otide 970 in Sox18 Ragl causes truncation of the transcriptional trans-activation domain, while the deletion of a cytosine residue at coding nucleotide 1048 in Sox18 Raop is beyond the previously determined limit of this domain (Hosking et al, 1995).…”

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confidence: 99%

Sox18 mutations in the ragged mouse alleles ragged‐like and opossum

James

Hosking

Gardner

et al. 2003

Genesis

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The ragged (Ra) spontaneous mouse mutant is characterised by abnormalities in its coat and cardiovascular system. Four alleles are known and we have previously described mutations in the transcription factor gene Sox18 in the Ra and Ra(J) alleles. We report here Sox18 mutations in the remaining two ragged alleles, opossum (Ra(op)) and ragged-like (Ragl). The single-base deletions cause a C-terminal frameshift, abolishing transcriptional trans-activation and impairing interaction with the partner protein MEF2C. The nature of these mutations, together with the near-normal phenotype of Sox18-null mice, suggests that the ragged mutant SOX18 proteins act in a dominant-negative fashion. The four ragged mutants represent an allelic series that reveal SOX18 structure-function relationships and implicate related SOX proteins in cardiovascular and hair follicle development.

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The phenogenetics of hair mutants in the house mouse: Opossum and Ragged

Cited by 15 publications

References 13 publications

The VCAM-1 Gene That Encodes the Vascular Cell Adhesion Molecule Is a Target of the Sry-related High Mobility Group Box Gene, Sox18

The VCAM-1 Gene That Encodes the Vascular Cell Adhesion Molecule Is a Target of the Sry-related High Mobility Group Box Gene, Sox18

Mice Null for Sox18 Are Viable and Display a Mild Coat Defect

Sox18 mutations in the ragged mouse alleles ragged‐like and opossum

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