Epidermal YAP2-5SA-ΔC Drives β-Catenin Activation to Promote Keratinocyte Proliferation in Mouse Skin In Vivo.
The epidermis is a highly regenerative tissue. YAP is a pivotal regulator of stem/progenitor cells in tissue regeneration, including in the epidermis. The molecular mechanisms downstream of YAP that activate epidermal cell proliferation remain largely unknown. We found that YAP and β-catenin co-localize in the nuclei of keratinocytes in the regenerating epidermis in vivo and in proliferating HaCaT keratinocytes in vitro. Inactivation of YAP in HaCaT keratinocytes resulted in reduced activated β-catenin and reduced keratinocyte numbers in vitro. In addition, we found that in the hyperplastic epidermis of YAP2-5SA-ΔC mice, the mutant YAP2-5SA-ΔC protein was predominantly localized in the keratinocyte nuclei and caused increased expression of activated nuclear β-catenin. Accordingly, β-catenin transcriptional activity was elevated in the skin of live YAP2-5SA-ΔC/TOPFLASH mice. Lastly, loss of β-catenin in basal keratinocytes of YAP2-5SA-ΔC/K14-creERT/CtnnB1-/-mice resulted in reduced proliferation of basal keratinocytes and a striking rescue of the hyperplastic abnormalities. Taken together, our work shows that YAP2-5SA-ΔC drives β-catenin activity to promote basal keratinocyte proliferation in the mouse skin in vivo. Our data shine new light on the etiology of regenerative dermatological disorders and other human diseases that display increased YAP and β-catenin activity.
School of Medical Sciences, UNSW Australia, Sydney, Australia.
Bassem
B
Akladios
School of Medical Sciences, UNSW Australia, Sydney, Australia.
Veronica
V
Mendoza-Reinoso
Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, Australia.
Michael S
MS
Samuel
School of Medical Sciences, UNSW Australia, Sydney, Australia.
Edna C
EC
Hardeman
University of Queensland Centre for Clinical Research and the Diamantina Institute, Brisbane, Australia.
Kiarash
K
Khosrotehrani
The School of Biomedical Sciences, The University of Queensland, Brisbane, Australia.
Brian
B
Key
School of Medical Sciences, UNSW Australia, Sydney, Australia; The School of Biomedical Sciences, The University of Queensland, Brisbane, Australia. Electronic address: a.beverdam@unsw.edu.au.
Annemiek
A
Beverdam
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins; D002460:Cell Line; D049109:Cell Proliferation; D004817:Epidermis / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism*; D012038:Regeneration; D012867:Skin / Q000378:metabolism*; D000091102:YAP-Signaling Proteins; D051176:beta Catenin / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C495267:CTNNB1 protein, mouse; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D051176:beta Catenin