Wnt5a exhibits layer-specific expression in adult skin, is upregulated in psoriasis, and synergizes with type 1 interferon.
BACKGROUND
Wnt5a is a member of the wingless-type patterning regulators important in pre-natal development. The expression and distribution of Wnt5a and its receptors frizzled (fzd) 3 and fzd 5 in adult human skin have not been comprehensively studied to date.


RESULTS
We here show that Wnt5a, fzd3, fzd5, as well as fzd6 are restricted to specific layers in normal epidermis, analogous to their zonal distribution in hair follicles, suggesting a role in adult skin differentiation. In line, Wnt5a and fzd5 are both overexpressed and re-distributed in the epidermis of psoriasis which involves disturbed keratinocyte differentiation. Functionally, Wnt5a lowers the concentration of IFN required to induce target genes, and increases the magnitude of IFN target gene induction, suggesting a molecular mechanism underlying IFN hypersensitivity in psoriasis. Finally, we identify nedd8 and the amyloid precursor APP, previously shown to be upregulated in psoriasis, as targets of synergistic IFNalpha/Wnt5a induction.


CONCLUSIONS
The present data (i) suggest that Wnt5a regulates epidermal differentiation even in adult skin and (ii) identify synergistic induction of type 1 IFN target genes as a novel mode of Wnt5a action. Targeting Wnt5a in the skin may reduce IFN hypersensitivity and be of therapeutical value.
Romanowska
Malgorzata
M
Division of Experimental Medicine, University of Dundee, Dundee, Scotland, UK.
Evans
Alan
A
Kellock
David
D
Bray
Susan E
SE
McLean
Kathleen
K
Donandt
Susanne
S
Foerster
John
J
D000328:Adult; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis; D002478:Cells, Cultured; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007370:Interferon Type I / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D000075687:NEDD8 Protein; D058255:Protease Nexins; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D011565:Psoriasis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D011994:Recombinant Proteins; D012867:Skin / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D014018:Tissue Distribution; D014162:Transfection; D014452:Ubiquitins / Q000096:biosynthesis; D015854:Up-Regulation; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism*; D000071818:Wnt-5a Protein
C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D051157:Frizzled Receptors; D007370:Interferon Type I; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D058255:Protease Nexins; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D014452:Ubiquitins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein