Yes-associated protein (YAP) transcriptional coactivator functions in balancing growth and differentiation in skin
Open accessAbstract
In mammals, skin begins as a single-layered epithelium, which, through a series of signals, either stratifies and differentiates to become epidermis or invaginates downward to make hair follicles (HFs). To achieve and maintain proper tissue architecture, keratinocytes must intricately balance growth and differentiation. Here, we uncover a critical and hitherto unappreciated role for Yes-associated protein (YAP), an evolutionarily conserved transcriptional coactivator with potent oncogenic potential. We show that YAP is highly expressed and nuclear in single-layered basal epidermal progenitors. Notably, nuclear YAP progressively declines with age and correlates with proliferative potential of epidermal progenitors. Shortly after initiation of HF morphogenesis, YAP translocates to the cytoplasm of differentiating cells. Through genetic analysis, we demonstrate a role for YAP in maintaining basal epidermal progenitors and regulating HF morphogenesis. YAP overexpression causes hair placodes to evaginate into epidermis rather than invaginate into dermis. YAP also expands basal epidermal progenitors, promotes proliferation, and inhibits terminal differentiation. In vitro gain-and-loss of function studies show that primary mouse keratinocytes (MKs) accelerate proliferation, suppress differentiation, and inhibit apoptosis when YAP is activated and reverse these features when YAP is inhibited. Finally, we identify Cyr61 as a target of YAP in MKs and demonstrate a requirement for TEA domain (TEAD) transcriptional factors to comediate YAP functions in MKs.
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Ccn1 is a YAP target gene often used as a readout for YAP-dependent transcription because of its strong response to YAP activity.
“Ccn1 is also a YAP target gene often used as a readout for YAP-dependent transcription because of its strong response to YAP activity (76).”
From Senescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2 (2022) · cites this paper as [76]
The Results identify Cyr61 (Ccn1) as a YAP target in epidermal cells and report that its expression rose more than twofold after YAP induction and was markedly reduced by YAP knockdown. The paper uses Cyr61 expression to assess YAP-dependent changes, but it does not establish that Ccn1 is often used as a transcriptional readout more generally. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCCN1 is a target of TAZ and YAP transcriptional co-activators, which act with transcription factors such as TEAD to regulate proliferation- and apoptosis-related genes.
“Recent genomic studies have also shown that CCN1 is a target of the TAZ and YAP transcriptional co-activators, which act in concert with various transcription factors such as TEAD to regulate expression of genes related to proliferation and apoptosis [45,46].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [46]
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- Authors
- Zhang, H., Pasolli, H. A., & Fuchs, E.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Fuchs, Elaine
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-01-24
- Volume
- 108
- Issue
- 6
- Pages
- 2270-2275
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3038759
- OpenAlex
- W1990486425
- Cited by
- 419
- References
- 28
- Citations by year
- 2026: 19 · 2025: 25 · 2024: 31 · 2023: 28 · 2022: 36 · 2021: 32 · 2020: 31 · 2019: 37 · 2018: 28 · 2017: 27 · 2016: 23 · 2015: 23 · 2014: 27 · 2013: 22 · 2012: 16
- FWCI
- 11.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Memorial Sloan-Kettering Cancer Center
- Starr Foundation
- National Cancer Institute (CA 09673, T32CA009673)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Health Sciences › Medicine › Urology › Hair Growth and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
- Keywords
- YAP, hair follicle morphogenesis, keratinocyte proliferation, keratinocyte differentiation, epidermal progenitors, basal epidermis, CYR61, TEAD transcription factors, skin development, aging, apoptosis
- MeSH terms
- YAP-Signaling Proteins, Animals, Cell Differentiation, Cells, Cultured, Embryo, Mammalian, Mice, Mutant Strains, Morphogenesis, Phosphoproteins, Stem Cells, Transcription, Genetic, Keratinocytes, Apoptosis, Cell Cycle Proteins, Hair Follicle, Adaptor Proteins, Signal Transducing, Cell Proliferation, Mice, Cysteine-Rich Protein 61
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