Corneodesmosin gene ablation induces lethal skin-barrier disruption and hair-follicle degeneration related to desmosome dysfunction.
Corneodesmosin (CDSN) is specific to desmosomes of epithelia undergoing cornification, mainly the epidermis and the inner root sheath of the hair follicles. CDSN nonsense mutations are associated with hypotrichosis simplex of the scalp, a rare disease that leads to complete baldness in young adults. CDSN displays adhesive properties, mostly attributable to its N-terminal glycine-rich domain, and is sequentially proteolyzed as corneocytes migrate towards the skin surface. K14-promoter driven Cre-mediated deletion of Cdsn in mice resulted in neonatal death as a result of epidermal tearing upon minor mechanical stress. Ultrastructural analyses revealed a desmosomal break at the interface between the living and cornified layers. After grafting onto nude mice, knockout skin showed a chronic defect in the epidermal permeability barrier. The epidermis was first hyperproliferative with a thick cornified layer, then, both the epidermis and the hair follicles degenerated. In adults, Cdsn deletion resulted in similar histological abnormalities and in a lethal barrier defect. We demonstrate that Cdsn is not essential for skin-barrier formation in utero, but is vital throughout life to preserve this barrier by maintaining desmosome integrity. The strong adhesive function that the protein confers on corneodesmosomes also seems necessary for maintaining the architecture of the hair follicle.
Leclerc
Emilie A
EA
UMR 5165 ;Différenciation Epidermique et Autoimmunité Rhumatoïde' (UDEAR), CNRS - Université Toulouse III, IFR150, INSERM, CHU PURPAN, Place du Dr Baylac, TSA 40031, F-31059 Toulouse, Cedex 9, France.
Huchenq
Anne
A
Mattiuzzo
Nicolas R
NR
Metzger
Daniel
D
Chambon
Pierre
P
Ghyselinck
Norbert B
NB
Serre
Guy
G
Jonca
Nathalie
N
Guerrin
Marina
M
D000818:Animals; D015153:Blotting, Western; D003896:Desmosomes / Q000378:metabolism / Q000648:ultrastructure*; D004817:Epidermis / Q000378:metabolism / Q000648:ultrastructure*; D005260:Female; D017353:Gene Deletion; D006023:Glycoproteins / Q000502:physiology*; D018859:Hair Follicle / Q000002:abnormalities*; D007039:Hypotrichosis / Q000235:genetics / Q000473:pathology*; D019426:Integrases / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016038:Skin Transplantation
D006023:Glycoproteins; D012333:RNA, Messenger; C529128:corneodesmosin protein, mouse; C045073:Cre recombinase; D019426:Integrases