title: Suppressing AP1 factor signaling in the suprabasal epidermis produces a keratoderma phenotype.
abstract: Keratodermas comprise a heterogeneous group of highly debilitating and painful disorders characterized by thickening of the skin with marked hyperkeratosis. Some of these diseases are caused by genetic mutation, whereas other forms are acquired in response to environmental factors. Our understanding of signaling changes that underlie these diseases is limited. In the present study, we describe a keratoderma phenotype in mice in response to suprabasal epidermis-specific inhibition of activator protein 1 transcription factor signaling. These mice develop a severe phenotype characterized by hyperplasia, hyperkeratosis, parakeratosis, and impaired epidermal barrier function. The skin is scaled, constricting bands encircle the tail and digits, the footpads are thickened and scaled, and loricrin staining is markedly reduced in the cornified layers and increased in the nucleus. Features of this phenotype, including nuclear loricrin localization and pseudoainhum (autoamputation), are characteristic of the Vohwinkel syndrome. We confirm that the phenotype develops in a loricrin-null genetic background, indicating that suppressed suprabasal AP1 factor function is sufficient to drive this disease. We also show that the phenotype regresses when suprabasal AP1 factor signaling is restored. Our findings suggest that suppression of AP1 factor signaling in the suprabasal epidermis is a key event in the pathogenesis of keratoderma.
authors: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors: Ellen A
authors: EA
authors: Rorke
authors: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors: Gautam
authors: G
authors: Adhikary
authors: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors: Christina A
authors: CA
authors: Young
authors: Department of Dermatology and Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA.
authors: Dennis R
authors: DR
authors: Roop
authors: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA; Department of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland, USA; Department of Obstetrics and Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA. Electronic address: reckert@umaryland.edu.
authors: Richard L
authors: RL
authors: Eckert
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000387:Ainhum / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D003251:Constriction, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004817:Epidermis / Q000473:pathology / Q000502:physiology*; D005260:Female; D006228:Hand Deformities, Congenital / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006319:Hearing Loss, Sensorineural / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007645:Keratoderma, Palmoplantar / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008817:Mice, Mutant Strains; D010641:Phenotype; D015398:Signal Transduction / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D018808:Transcription Factor AP-1; C064554:loricrin