Myodegeneration in EDA-A2 transgenic mice is prevented by XEDAR deficiency.
EDA-A1 and EDA-A2 are members of the tumor necrosis factor family of ligands. The products of alternative splicing of the ectodysplasin (EDA) gene, EDA-A1 and EDA-A2 differ by an insertion of two amino acids and bind to distinct receptors. The longer isoform, EDA-A1, binds to EDAR and plays an important role in sweat gland, hair, and tooth development; mutations in EDA, EDAR, or the downstream adaptor EDARADD cause hypohidrotic ectodermal dysplasia. EDA-A2 engages the receptor XEDAR, but its role in the whole organism is less clear. We have generated XEDAR-deficient mice by gene targeting and transgenic mice expressing secreted forms of EDA-A1 or EDA-A2 downstream of the skeletal muscle-specific myosin light-chain 2 or skin-specific keratin 5 promoter. Mice lacking XEDAR were indistinguishable from their wild-type littermates, but EDA-A2 transgenic mice exhibited multifocal myodegeneration. This phenotype was not observed in the absence of XEDAR. Skeletal muscle in EDA-A1 transgenic mice was unaffected, but their sebaceous glands were hypertrophied and hyperplastic, consistent with a role for EDA-A1 in the development of these structures. These data indicate that XEDAR-transduced signals are dispensable for development of ectoderm-derived organs but might play a role in skeletal muscle homeostasis.
Newton
Kim
K
Molecular Oncology Department, Genentech, Inc., South San Francisco, California 94080, USA.
French
Dorothy M
DM
Yan
Minhong
M
Frantz
Gretchen D
GD
Dixit
Vishva M
VM
D000818:Animals; D002478:Cells, Cultured; D053331:Ectodysplasins; D053339:Edar Receptor; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology*; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D053338:Receptors, Ectodysplasin; D018124:Receptors, Tumor Necrosis Factor; D012627:Sebaceous Glands / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D053340:Xedar Receptor
C506018:EDA protein, human; C506011:EDA2R protein, human; C506008:EDAR protein, human; D053331:Ectodysplasins; C506019:Eda protein, mouse; C506015:Eda2r Protein, mouse; D053339:Edar Receptor; C506009:Edar protein, mouse; D008565:Membrane Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D053338:Receptors, Ectodysplasin; D018124:Receptors, Tumor Necrosis Factor; D053340:Xedar Receptor