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Bai, R.; Guo, Y.; Liu, W.; Song, Y.; Yu, Z.; Ma, X. WNT Signaling Pathways in Skin Development. Encyclopedia. Available online: https://encyclopedia.pub/entry/52389 (accessed on 14 June 2024).
Bai R, Guo Y, Liu W, Song Y, Yu Z, Ma X. WNT Signaling Pathways in Skin Development. Encyclopedia. Available at: https://encyclopedia.pub/entry/52389. Accessed June 14, 2024.
Bai, Ruoxue, Yaotao Guo, Wei Liu, Yajuan Song, Zhou Yu, Xianjie Ma. "WNT Signaling Pathways in Skin Development" Encyclopedia, https://encyclopedia.pub/entry/52389 (accessed June 14, 2024).
Bai, R., Guo, Y., Liu, W., Song, Y., Yu, Z., & Ma, X. (2023, December 05). WNT Signaling Pathways in Skin Development. In Encyclopedia. https://encyclopedia.pub/entry/52389
Bai, Ruoxue, et al. "WNT Signaling Pathways in Skin Development." Encyclopedia. Web. 05 December, 2023.
WNT Signaling Pathways in Skin Development
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The WNT signaling pathway plays a critical role in a variety of biological processes, including development, adult tissue homeostasis maintenance, and stem cell regulation. Variations in skin conditions can influence the expression of the WNT signaling pathway.

WNT signaling pathway β-catenin skin development

1. Introduction

WNT signaling pathways are crucial aspects of cellular biology and have been evolutionarily conserved across different species. These pathways have a significant impact on gene expression and play a role in regulating the cytoskeleton and mitotic spindle [1]. In addition to coordinating complex cellular behavior during development, WNT signaling pathways also control cell proliferation, stem cell maintenance, cell fate decisions, organized cell movement, and tissue polarity establishment during skin wound repair and mechanical stretching [2].

2. Overview of WNT Signaling Pathways

2.1. WNT Signaling Pathways

Secreted WNT family signaling proteins bind to transmembrane frizzled protein (FZ) receptors on the cell membrane to form WNT/FZ complexes, which activate intracellular signaling pathways. Depending on the signaling pathways activated by different WNT/FZ complexes, they are generally classified as canonical or non-canonical WNT signaling pathways [3]. Canonical WNT signaling pathways usually consist of four key components, namely low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6), FZ, WNT, and β-catenin [4] (Figure 1).
Figure 1. WNT/β-catenin signaling pathway. In the absence of WNT signaling, β-catenin forms complexes with several other proteins in the cytoplasm, including APC, Axin, CK, and GSK-3β, leading to the compound phosphorylation and degradation of free β-catenin in the cytoplasm. In the presence of WNT signaling, WNT can bind to the FZ/LRP5/6 complex and recruit Axin to phosphorylated Dsh. This behavior can inhibit GSK3 activity and prevent the degradation of β-catenin by the APC/Axin/GSK-3β complex, thereby increasing free β-catenin in the cytoplasm. B-catenin translocates to the nucleus through nuclear pores and forms complexes with TCF/LEF to activate downstream target gene transcription, thereby promoting cell proliferation. The primary regulators of the WNT/β-catenin signaling pathway are DKK, SFRP, and APCDD1. DKK belongs to a family of secreted WNT inhibitors that attenuate WNT/β-catenin signaling by binding to and internalizing LRP5/6 coreceptors on the cell surface. The SFRP family can combine with the FZ receptor or WNT ligands, enable antagonism or excitement, and adjust the WNT signaling pathway. APCDD1 is a membrane-bound glycoprotein in HFs. APCDD1 decreases WNT signaling by binding to both LRP5 and WNT3a.
As a cell surface endocytotic receptor, LRP5/6 is indispensable in the canonical WNT signaling pathway [5]. LRP5/6 is a single-pass transmembrane protein with an extracellular domain and contains four β-propeller region/epidermal growth factor (EGF) repeats and three tandem ligand-binding repeats [6]. WNT ligands and antagonists can bind to the four β-propeller/EGF regions of LRP5/6. Then, the bound LRP5/6/WNT/FZ complex causes a conformational change in the tail of LRP5/6; this change subsequently results in phosphorylation and axon-binding of LRP5/6, ultimately activating the canonical WNT pathway [6][7]. The FZ is a cell surface receptor consisting of an extracellular WNT-binding cysteine-rich domain, a transmembrane domain of seven helices, and a cellular tail. A total of 10 FZs have been identified in mice and humans. The canonical WNT protein binds to the FZ receptor and activates β-catenin/T-cell factor (TCF), whereas the non-canonical WNT protein binds to the FZ receptor and activates the small Rho GTPase, c-jun N-terminal kinase, and other β-linker-independent signaling events [2]. The WNT protein, a secreted glycoprotein encoded by a highly conserved gene family, attaches to receptor complexes consisting of FZ family receptors and/or co-receptors to initiate the WNT signaling pathway [8]. Various WNT proteins are expressed in different spaces and times and play different roles [8]. So far, 19 distinct WNT protein-coding genes have been found in mice and humans. Among them, WNT1, WNT3, WNT3a, WNT7a, WNT7b, WNT8, and WNT10b can activate the canonical WNT signaling pathway [3][4][9][10]. The key to stable exportation of the WNT/β-catenin pathway is β-catenin. Β-catenin is both an effector of mechanical signals and a cytoplasmic/nuclear protein, and it has two forms in the plasma membrane, namely the E-calmodulin/β-catenin/α-catenin complex and free β-catenin [8][11]. When no WNT signal is present, β-catenin binds to E-calmodulin and α-catenin complexes through adherens junctions and participates in intercellular adhesion, migration, and cell–cell adhesion mechanotransduction [12]. When WNT signaling is present, β-catenin is a core member of the WNT/β-catenin signaling pathway and promotes the transcription of target genes, thereby regulating cell proliferation [11].
In the absence of WNT signaling, β-catenin in the cytoplasm forms a complex with several other proteins, including adenoma polyp protein (APC), Axin, casein kinase (CK), and glycogen synthase kinase-3β (GSK-3β). This complex leads to the phosphorylation and degradation of β-catenin through ubiquitination and proteasomal degradation [13]. WNT signaling, however, can prevent this degradation by affecting the cytoplasmic proteins that regulate β-catenin stability. The binding of WNT to the FZ/LRP5/6 complex results in the phosphorylation of Dishevelled (Dsh) and the recruitment of Axin to phosphorylated Dsh. This leads to the inhibition of GSK3 activity and prevents β-catenin degradation via the APC/Axin/GSK-3β complex [14][15][16]. B-catenin accumulation in the cytoplasm, triggered by the presence of WNT signaling, leads to the transfer of β-catenin into the nucleus through nuclear pores. Once in the nucleus, β-catenin forms a complex with TCF/lymphocyte-enhancing factor (LEF) and converts the TCF repressor complex into a transcriptional activator complex [15]. This complex activates the transcription of genes such as c-myc and cyclin D1, which promotes cell proliferation and helps maintain stem cell communities [17][18].
Non-canonical WNT signaling can be categorized as WNT/calcium (Ca2+) or WNT/planar cell polarity (PCP) signaling pathways. In WNT/Ca2+ signaling, WNT ligand–receptor interactions lead to the release of intracellular calcium, thereby activating calmodulin-dependent protein kinase II (CaMKII), calcineurin (CaN), or protein kinase C (PKC). Among these effectors, CaMKII triggers the TAK1-NLK cascade, which suppresses the transcriptional activity of WNT/β-catenin signaling. WNT/PCP pathways involve the activation of small GTPases Rho, Rac, and Cdc42 and their downstream JNK signaling, which regulate cytoskeleton rearrangement and planar cell polarity (PCP). Non-canonical WNT pathways also play an important role in skin development and disease occurrence [8].
Studies have shown that during skin morphogenesis, the WNT/β-catenin signaling pathway determines the formation of hair placenta and dermal papillary precursor dermal agglutinates. Subsequently, in a mature individual, the WNT/β-catenin signaling pathway maintains hair regeneration in hair follicle precursor cells and dermal papilla. In addition, WNT/β-catenin regulates basal layer cell proliferation to maintain skin homeostasis in a pathological state [19]. As evidenced, the WNT/β-catenin signaling pathway has a vital function in skin development and physiological state maintenance.

2.2. Regulation of the WNT Signaling Pathway

The WNT signaling pathway plays an important role in regulating skin development and maintaining homeostasis. A better understanding of the complex regulation of this pathway may have important implications for the treatment of skin-related disorders. The WNT signaling pathway is regulated by various factors including dickkopf (DKK), secretory frizzled-related proteins (SFRPs), and adenomatosis polyposis coli down-regulated 1 (APCDD1).

2.2.1. DKK

DKK belongs to the secretory WNT inhibitor family and has four members (DKK1–4) [20][21]. By binding to and internalizing LRP5/6 coreceptors on the surface of cells, DKKs weaken WNT/β-catenin signal transduction [6]. DKK1 can diffuse in vivo and exhibits an extremely powerful WNT inhibitory effect [22][23]. In early development, the ectopic expression of DKK1 in the skin results in the loss of expression of β-catenin and LEF-1 in the dermis and terminates subsequent basement membrane formation [22]. In contrast, DKK1 expression is low in interfollicular skin [22]. DKK4 is a potential regulator of WNT signaling, not only during the morphogenesis of HF, but also in other ectodermal appendages [23]. The specific mechanism behind this may be that DKK4 facilitates the transition from classic WNT signals to non-classic WNT signals [24]. However, not all DKKs can suppress the classic WNT signaling pathway. DKK2 is an environment-dependent WNT inhibitor. The expression levels of different DKK receptors determine DKK2′s ability to act as both an activator and an inhibitor of the WNT/β-catenin signaling pathway [23][25]. In addition, DKK3, which has the lowest homology compared to other DKKs, does not exhibit an inhibitory effect on the WNT signaling pathway [23][26].

2.2.2. SFRPs

SFRPs are glycoproteins that contain frizzled cysteine-rich structural domains, which are highly homologous to FZ receptors [27]. They are powerful signaling molecules that function upstream of WNT signaling. SFRPs have multiple biological roles in different cellular processes, including tissue development and tissue homeostasis [28][29]. Due to the presence of frizzled cysteine-rich structural domains, they can bind to FZ receptors or WNT ligands, making them effective WNT signaling regulators [30]. There are five proteins in the SFRP family: SFRP1, SFRP2, SFRP3, SFRP4, and SFRP5. These SFRPs mainly function as antagonists in similar ways (Table 1), while SFRP2, a crucial member of the SFRP family, can act as both an antagonist and an agonist of WNT signaling. SFRP2 overexpression chelates WNT ligands to prevent WNT ligands binding to FZ receptors and reduce β-catenin levels, thereby preventing WNT/β-catenin pathway overactivation and inhibiting cell proliferation and migration. However, it has also been found that SFRP2 may exert an agonistic effect on the WNT signaling pathway by directly binding to the FZ receptor [31][32]. SFRP1, SFRP3, SFRP4, and SFRP5 are all WNT signaling antagonists. Overexpression of these antagonists can inactivate the WNT/β-catenin signaling pathway. Among them, SFRP1 and SFRP5 are highly similar structurally to FZ receptors and inhibit WNT signaling by binding to WNT proteins and FZ receptors [27][33][34][35][36][37].
Table 1. Roles of DKK and SFRP in the WNT/β-catenin signaling pathway.

2.2.3. APCDD1

APCDD1 is a gene that is mutated in human hair and skin disorders. It encodes a membrane-bound glycoprotein that can be abundantly expressed in human HFs. The APCDD1 protein can interact with WNT3A and LRP5, two important components of WNT signaling. APCDD1 binds to LRP5 to form a complex and decreases WNT signaling outputs upon activation by WNT3a ligands. APCDD1 is also the intersection point of the WNT/BMP pathway. APCDD1 can coordinate WNT/BMP activation, which may dynamically explain periodic sequential WNT/BMP activation during the hair cycle [41][42].

3. The Role of WNT Signaling in Skin Development

Mammalian skin is composed of three main layers, namely the epidermis, dermis, and subcutaneous tissue. The epidermis and its derived appendages, such as hair follicles (HFs), sebaceous glands (SGs), and sweat glands (SwGs), work together to protect the body from environmental stress. The underlying dermis contains nourishing blood vessels and protein fibers. Subcutaneous tissue is adipose tissue that provides thermal insulation and energy resources [8]. WNTs play an important role in numerous cellular processes during skin development. Several molecules can regulate the WNT signaling pathway to play an essential role in the development of fibroblasts, epidermal stem cells (ESCs), and hair follicle stem cells (HFSCs).

3.1. Epidermal Development

In the early stage of skin development, communication between the embryonic epidermis and dermis is essential for basement membrane formation, epidermal stratification, and HF induction [8][43]. After gastrulation, embryonic cells differentiate into the epidermis and dermis. WNT signaling directs ectodermal cells to form the skin epithelium, which inhibits the ectodermal response to fibroblast growth factors (FGFs). In the absence of FGF signaling, ectodermal cells can express bone morphogenic proteins (BMPs) that guide cell differentiation into K8/K18 keratin-expressing cells, known as keratinocytes (KCs), forming the basal layer of the embryonic epidermis [44]. The basal layer of the epidermis produces a basement membrane—the physical boundary between the epithelium and the dermis—which is rich in extracellular matrix proteins and growth factors [45]. The KCs then differentiate into intermediate layer cells, which mature into heckle and granular cells before finally forming the KC envelope to execute the skin’s barrier function [46]. The development of the epidermis depends on strong WNT/β-catenin signaling. The stem cell properties of epidermal basal cells are related to WNT/β-catenin pathway activity [8]. The interfollicular epithelium (IFE) continues to grow and multiply to form new epidermis, and basal layer stem cells (SCs) continue to replenish the IFE via the hierarchical and stochastic models [47][48]. However, β-catenin overexpression in basal cells leads to serious overproliferation in the epidermis [49]. During epidermal development, WNT ligands can inhibit WNT/β-catenin signaling. WNT5a phosphorylates receptor-related orphan receptor α (RORα). The phosphorylated RORα then binds to β-catenin to form a transcription complex that inhibits WNT/β-catenin transcriptional activity [50]. In addition, WNT5a can induce ROR2–DVL interactions which negatively regulate the transcriptional activity of WNT/β-catenin signals by activating ROR2 [51].

3.2. Dermal Development

During development, the mesoderm divides into somites. Then, somites form the inner layer of the dermis (with proliferative potential) and an upper layer of differentiated cells [8][52]. Meanwhile, WNT signals also direct mesenchymal cells to form the dermis [52][53]. The dermis is mainly composed of dermal fibroblasts (DFs) and the extracellular matrix (ECM). DF differentiation and mutual signals with epidermal KCs are an integral part of skin formation and appendage development [54][55]. During the embryonic stage, DF precursors migrate from the somite to the subepidermis and subsequently differentiate into DF progenitors [54][56]. Then, DF progenitors differentiate into papillary fibroblast progenitors (PPs), reticular fibroblast progenitors (RPs), and hair dermal papillary fibroblasts (DPs). PPs differentiate into papillary fibroblasts and DPs, which are essential for communicating with epidermal signals and stimulating HF morphogenesis [57][58]. RPs differentiate into dermal white adipose tissue (DWAT), which helps insulate the skin, and reticular fibroblasts, which secrete dense collagen fibers that provide elasticity to the skin [57][59]. According to research by Gupta et al., DF progenitors which express WNT signaling can produce PPs and dermal condensates, which then differentiate into DPs and help to initiate skin HF development [60][61]. In addition, WNT signaling and BMP signaling are required to jointly maintain DP-induced HF formation [48]. Many key transcription factors and signaling factors are involved in DF progenitor cell development. Among them, WNT/β-catenin signaling regulates several transcription factors essential for DF development, such as Lef1, En1, Msx1, Msx2, Twist1, and Twist2 [62][63][64]. The transcription factor LEF1 expresses embryonic and neonatal papillary fibroblasts and is absent in adult fibroblasts [56]. LEF1 plays a crucial role in fibroblast development and guides different fibroblast cell lines to produce WNT/β-catenin-specific responses [64].

3.3. Development of Skin Appendages

3.3.1. HF Formation

HF formation is a complex process resulting from interactions between the embryonic epidermis and dermis. These interactions are brought about through three stages, comprising hair placentation, hair organogenesis, and cell differentiation [65][66]. In the early stages, dermal fibroblasts receive WNT signals from the embryonic epidermis and respond by producing their own WNT signals, which in turn cause epidermal basal cells to gather and form a hair bud. The developing placenta produces more WNT ligands, which cause mesenchymal cells to form dermal condensates and the hair placenta. These cells rapidly divide and wrap around the dermal condensate, forming the HF dermal papilla [8]. Epidermal cells continue to penetrate the dermis and differentiate into mature HF inner root sheaths and hair shafts [52]. SCs in the HF can be divided into two groups: HFSCs located in the outer layer of the bulge, and stem cells located in the secondary hair germ below the bulge [47]. WNT/β-catenin signals are crucial for HFSC specification and differentiation; overexpression of these signals in embryonic epidermal cells abolishes HFSC specification and inhibits stem cell marker expression [67][68]. However, WNT5a overexpression in developing skin inhibits HFSC formation, while WNT10-mediated WNT activation increases the proportion of CD34+ HFSCs and results in enlargements of hairballs, hair shafts, and the dermal papillae [69][70].

3.3.2. Development of SGs and SwGs

The development of SGs and SwGs is highly related to the development of HFs. The WNT/β-catenin signaling pathway can regulate this process. During SG development, the downstream mediators of WNT/β-catenin signaling and hedgehog (Hh) signaling are regulated by TCF3/Lef1 transcription factors, thereby affecting cell proliferation and differentiation [71]. The WNT signaling pathway regulator DKK4 exhibits high expression levels during SwG growth, which inhibits the traditional WNT signaling pathway [72]. In addition, Eda signaling and Shh signaling are also involved in the regulation of SwG formation [72]. It is clear that the WNT signaling pathway induces initial skin development and plays an important role in basement membrane formation, epidermal stratification, and HF induction. Different signaling molecules either positively or negatively regulate the WNT/β-catenin signaling pathway to maintain an appropriate expression level suitable for skin cell development.

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