Expression of desmoglein 1 compensates for genetic loss of desmoglein 3 in keratinocyte adhesion.
The desmoglein compensation hypothesis, namely that one desmoglein can compensate for loss of function of another, has been proposed to explain the tissue specificity of the autoantibody-induced loss of cell adhesion in pemphigus. To validate this hypothesis genetically, we used desmoglein-3 knockout mice (DSG3-/-) that lose their telogen hair prematurely due to loss of adhesion between keratinocytes of the telogen hair club and the outer root sheath, where the only desmoglein expressed in normal mice is desmoglein-3. To determine if desmoglein-1 could substitute for the function of desmoglein-3 in telogen hair, we produced transgenic mice that express desmoglein-1 driven off the keratin 14 promoter, and then bred the transgene (TG) into DSG3-/- mice. Immunoblotting showed transgene expression in skin, and immunofluorescence showed desmoglein-1 in the telogen club of DSG3-/-TG+ but not DSG3-/-TG- mice. DSG3-/-TG- mice lost telogen hair with each wave of telogen, whereas DSG3-/-TG+ mice had markedly delayed and decreased hair loss. DSG3-/- mice also show low weights due to blisters in the oral mucosa. Surprisingly, DSG3-/-TG+ mice showed similar low weights, because the transgene, although expressed in skin, was not well expressed in oral mucous membranes. These studies show that desmoglein-1 can compensate for loss of desmoglein-3-mediated adhesion, and provide genetic evidence confirming the desmoglein compensation hypothesis.
Hanakawa
Yasushi
Y
Department of Dermatology, University of Pennsylvania, 415 Curie Boulevard, Philadelphia, PA 19104, U.S.A.
Matsuyoshi
Norihisa
N
Stanley
John R
JR
D000818:Animals; D001768:Blister / Q000473:pathology; D001947:Breeding; D015820:Cadherins / Q000235:genetics*; D002448:Cell Adhesion / Q000502:physiology; D051183:Desmoglein 1; D051184:Desmoglein 3; D003896:Desmosomes / Q000473:pathology; D005260:Female; D015870:Gene Expression / Q000502:physiology; D018859:Hair Follicle / Q000166:cytology; D053547:Keratin-14; D015603:Keratinocytes / Q000166:cytology*; D007633:Keratins / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009061:Mouth Mucosa / Q000473:pathology; D010392:Pemphigus / Q000235:genetics* / Q000473:pathology*; D010641:Phenotype; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000502:physiology; D019076:Transgenes / Q000502:physiology; D015431:Weight Loss / Q000235:genetics
D015820:Cadherins; C071894:DSG3 protein, human; D051183:Desmoglein 1; D051184:Desmoglein 3; C507540:KRT14 protein, human; D053547:Keratin-14; C507446:Krt14 protein, mouse; D007633:Keratins