The Roles of YAP/TAZ and the Hippo Pathway in Healthy and Diseased Skin

Abstract

Skin is the largest organ of the human body. Its architecture and physiological functions depend on diverse populations of epidermal cells and dermal fibroblasts. Reciprocal communication between the epidermis and dermis plays a key role in skin development, homeostasis and repair. While several stem cell populations have been identified in the epidermis with distinct locations and functions, there is additional heterogeneity within the mesenchymal cells of the dermis. Here, we discuss the current knowledge of how the Hippo pathway and its downstream effectors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) contribute to the maintenance, activation and coordination of the epidermal and dermal cell populations during development, homeostasis, wound healing and cancer.

Keywords: Hippo signalling; fibroblasts; fibrosis; skin cancer; skin development; stem cells; wound healing.

Figure 1

Morphology of the skin. The epidermis and dermis are separated by a BM. In the epidermis, multiple spatially distinct stem cell populations have been identified in the hair follicle bulge, isthmus and sebaceous gland, and their characteristic markers are shown in the colour coded legend. In the dermis, papillary fibroblasts are located in proximity to the BM and are embedded in thin collagen fibres. Reticular fibroblasts populate the central dermis and are surrounded by thick collagen bundles (grey). Preadipocytes are close to the DWAT where the mature adipocytes reside. In addition, specialised fibroblast subpopulations associate with the HF give rise to the DP, DS and APM. Endothelial cells form the blood vessels which are surrounded by pericytes. Sensory neurons are associated with the HF upper bulge SC population and different immune cell types populate different regions of the skin. Abbreviations: APM, arrector pili muscle; BM, basement membrane; Bu, bulge; DP, dermal papilla; DS, dermal sheath; DWAT, dermal white adipose tissue; SG, sebaceous gland.

Figure 2

Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) activity in the IFE and HF development. (A) The IFE is a stratified squamous epithelium. It is divided into four main layers that are distinguished morphologically according to the differentiation status of the keratinocytes as they cease to proliferate and move upward to produce the skin’s barrier. Note that in adult IFE nuclear YAP/TAZ are restricted in cell clusters of the basal layer. (B) Early skin and HF development. During early skin development, cells of the epidermis and dermis are highly proliferative and highly positive for nuclear YAP/TAZ. Once the epidermis starts to stratify, only the proliferative cells in the basal layer maintain nuclear YAP/TAZ. HF development is initiated by an epidermal–mesenchymal cross-talk inducing condensation of mesenchymal cells beneath the BM which leads to the formation of a HF placode (HF stages 0–1). The HF placodes further matures into a hair germ (HF stages 1–2), which start to engulf the dermal papilla fibroblasts (HF stages 3–4). At HF stages 5–6 the dermal papilla is fully encapsulated; the HF epithelial cells differentiate into the distinct HF layers and the bulge and SG start to form. All cell compartments are clearly visible at HF stage 7–8 and the HF shaft emerges through the epidermis. YAP is nuclear in the placode and hair germ cells of the epidermis and dermis (HF stage 0–2) and then becomes more restricted to the highly proliferative basal epithelial cells (HF stage 3–8). YAP/TAZ are highly nuclear in the HF matrix, and there are additional cell cluster with nuclear YAP in the IFE and SG. Note that due to its wide-spread expression in skin, only nuclear YAP/TAZ are shown to indicate sites of YAPTAZ activity. Abbreviations: BM, basement membrane; Bu, bulge; DP, dermal papilla; HF, hair follicle; HG, hair germ; HS, hair shaft; IFE, interfollicular epidermis; IRS, inner root sheath; Mx matrix; ORS outer root sheath; SG, sebaceous gland.

Figure 3

YAP localisation during HF cycling. (A,B) Schematic of a HF in the resting phase (telogen) (A) and growth phase (anagen) (B). In telogen phase, YAP is mainly localised to the cytoplasm in bulge and DP cells and there are only scattered cluster of cells with nuclear YAP in the IFE and SG. During anagen the highly proliferative cells of the ORS and HF matrix display strong nuclear YAP localisation, while YAP is cytoplasmatic in differentiating cells of the IRS and HS. Beside cell clusters with nuclear YAP in the IFE and SG during anagen, some DP cells also display YAP in the nucleus. Note that only nuclear YAP is shown. (C) Immunostaining for YAP (red) and Itga6 (green) of mouse skin during telogen, early anagen and full anagen. Nuclei are stained with DAPI (blue). Note, the strong increase in nuclear YAP in the HG and infundibulum during anagen induction. Scale bars, 50 µm. Abbreviations: Bu, bulge; DP, dermal papilla; HF, hair follicle; HG, hair germ; HS, hair shaft; IFE, interfollicular epidermis; IRS, inner root sheath; Mx matrix; ORS outer root sheath; SG, sebaceous gland.

Figure 4

Regulation of YAP/TAZ in epidermal cells. Hippo signalling via MOB1A/MOB1B and LATS1/LATS2 inhibits YAP/TAZ via serine phosphorylation (yellow) to promote cytoplasmic retention. The kinases activating MOB1A/MOB1B and LATS1/LATS2 are not known. Integrin (ITG)–SRC signalling promotes YAP/TAZ nuclear localisation and TEAD binding. SRC can directly phosphorylate YAP/TAZ on tyrosine residues (orange) but may also act indirectly to activate Hippo signalling. A contractile F-actin-myosin cytoskeleton helps stabilise ITGβ1 adhesions and thus may contribute to SRC activation, while ITGβ4 adhesions are part of hemidesmosomal complexes that are stabilised by keratin intermediate filaments (not shown). At adherens junctions, α-catenin controls YAP/TAZ activity and phosphorylation by modulating its interaction with 14-3-3 and the PP2A phosphatase. In proliferating cells of the sebaceous gland, activation of caspase-3 cleaves α-catenin, thus facilitating the activation and nuclear translocation of YAP/TAZ. α-catenin can also inhibit ITGβ4-mediated direct activation of SRC. Putative nuclear interactions of YAP/TAZ with other transcription factors are also indicated.