Suprabasal desmoglein 3 expression in the epidermis of transgenic mice results in hyperproliferation and abnormal differentiation.
The desmoglein 1 (Dsg1) and desmocollin 1 (Dsc1) isoforms of the desmosomal cadherins are expressed in the suprabasal layers of epidermis, whereas Dsg3 and Dsc3 are more strongly expressed basally. This differential expression may have a function in epidermal morphogenesis and/or may regulate the proliferation and differentiation of keratinocytes. To test this hypothesis, we changed the expression pattern by overexpressing human Dsg3 under the control of the keratin 1 (K1) promoter in the suprabasal epidermis of transgenic mice. From around 12 weeks of age, the mice exhibited flaking of the skin accompanied by epidermal pustules and thinning of the hair. Histological analysis of affected areas revealed acanthosis, hypergranulosis, hyperkeratosis, localized parakeratosis, and abnormal hair follicles. This phenotype has some features in common with human ichthyosiform diseases. Electron microscopy revealed a mild epidermal spongiosis. Suprabasally, desmosomes showed incorporation of the exogenous protein by immunogold labeling but were normal in structure. The epidermis was hyperproliferative, and differentiation was abnormal, demonstrated by expression of K14 in the suprabasal layer, restriction of K1, and strong induction of K6 and K16. The changes resembled those found in previous studies in which growth factors, cytokines, and integrins had been overexpressed in epidermis. Thus our data strongly support the view that Dsg3 contributes to the regulation of epidermal differentiation. Our results contrast markedly with those recently obtained by expressing Dsg3 in epidermis under the involucrin promoter. Possible reasons for this difference are considered in this paper.
School of Biological Sciences, University of Manchester, Manchester, United Kingdom.
Anita J
AJ
Merritt
Mohamed Y
MY
Berika
Wenwu
W
Zhai
Sarah E
SE
Kirk
Baijing
B
Ji
Matthew J
MJ
Hardman
David R
DR
Garrod
D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D051187:Desmocollins; D051183:Desmoglein 1; D051184:Desmoglein 3; D051182:Desmogleins; D051180:Desmoplakins; D003896:Desmosomes / Q000378:metabolism; D004817:Epidermis / Q000473:pathology / Q000502:physiology* / Q000648:ultrastructure; D006801:Humans; D015603:Keratinocytes / Q000502:physiology; D007633:Keratins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D010392:Pemphigus / Q000235:genetics
D001324:Autoantigens; D015820:Cadherins; D003598:Cytoskeletal Proteins; C495297:DSG1 protein, human; C071894:DSG3 protein, human; D051187:Desmocollins; D051183:Desmoglein 1; D051184:Desmoglein 3; D051182:Desmogleins; D051180:Desmoplakins; C495299:Dsg1a protein, mouse; C495300:Dsg3 protein, mouse; D007633:Keratins