To Control Site-Specific Skin Gene Expression, Autocrine Mimics Paracrine Canonical Wnt Signaling and Is Activated Ectopically in Skin Disease.
Despite similar components, the heterogeneity of skin characteristics across the human body is enormous. It is classically believed that site-specific fibroblasts in the dermis control postnatal skin identity by modulating the behavior of the surface-overlying keratinocytes in the epidermis. To begin testing this hypothesis, we characterized the gene expression differences between volar (ventral; palmoplantar) and nonvolar (dorsal) human skin. We show that KERATIN 9 (KRT9) is the most uniquely enriched transcript in volar skin, consistent with its etiology in genetic diseases of the palms and soles. In addition, ectopic KRT9 expression is selectively activated by volar fibroblasts. However, KRT9 expression occurs in the absence of all fibroblasts, although not to the maximal levels induced by fibroblasts. Through gain-of-function and loss-of-function experiments, we demonstrate that the mechanism is through overlapping paracrine or autocrine canonical WNT-β-catenin signaling in each respective context. Finally, as an in vivo example of ectopic expression of KRT9 independent of volar fibroblasts, we demonstrate that in the human skin disease lichen simplex chronicus, WNT5a and KRT9 are robustly activated outside of volar sites. These results highlight the complexities of site-specific gene expression and its disruption in skin disease.
Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, Maryland.
Dongwon
D
Kim
Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, Maryland.
M Zulfiquer
MZ
Hossain
Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, Maryland.
Ashley
A
Nieves
Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, Maryland.
Lihong
L
Gu
Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, Maryland.
Tabetha S
TS
Ratliff
Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, Maryland.
Seung
S
Mi Oh
Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, Maryland.
Angela
A
Park
Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, Maryland.
Seunghyun
S
Han
Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, Maryland.
Nicole B
NB
Yang
Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, Maryland.
Ji
J
Qi
Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, Maryland.
Janis M
JM
Taube
Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, Maryland.
Sewon
S
Kang
Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, Maryland. Electronic address: lag@jhmil.edu.
Luis A
LA
Garza
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D005455:Fluorescent Antibody Technique; D005533:Foot Dermatoses / Q000378:metabolism*; D015870:Gene Expression / Q000502:physiology; D055785:Gene Knockdown Techniques; D006229:Hand Dermatoses / Q000378:metabolism*; D006801:Humans; D053555:Keratin-5 / Q000378:metabolism; D053534:Keratin-9 / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D009450:Neurodermatitis / Q000378:metabolism; D011565:Psoriasis / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012867:Skin / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000235:genetics / Q000502:physiology*; D000071818:Wnt-5a Protein / Q000378:metabolism; D051176:beta Catenin / Q000502:physiology
D053555:Keratin-5; D053534:Keratin-9; D012333:RNA, Messenger; D000071818:Wnt-5a Protein; D051176:beta Catenin