Skin provides protect for animals from change in temperature, radiation, UV rays from the sun, trauma, and infections, and it allows animals to perceive their environment through their tactile sense. Skin provides a camouflage for animals excluding humans because the skin is utilized as protection against predators and aids as decoration for social and reproductive behavior such as a peacock. Skin stem cells are multipotent stem cells that are present in epidermis that possess the ability to self-renew and differentiate into different cell lineages of the skin.5 In order for skin stem cells to be produced, skin stem cells have to undergo embryogenesis.
The early stages of skin development involve the complex and dynamic cross-talking between the embryonic epidermis and the dermis. The inter-tissue communication between the embryonic epidermis and the dermis provides instructions for many things such as the basement membrane formation, stratification of the epidermis and hair follicle (HF) induction. However, the main focus are the basement membrane formation and the stratification of the epidermis. In early stages of embryogenesis, the surface of the embryo is covered by a single ectodermal layer which is the outermost layers of the three primary germ layers. Ectoderm gives rise to the nervous system and the skin epithelium.
The specification of the ectodermal cells into the epidermal layer known as skin is governed by Wnt signaling stimulation which helps inhibit the response of ectoderm to fibroblast growth factors (FGFs).25 Without FGFs signaling, the ectodermal cells can express bone morphogenetic proteins (BMPs) and will start to form the epidermal characteristics.25,26.
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The ectoderm layer splitting into hair formation and skin epithelium (epidermal basal layer) that initiates the stratification of epidermis. Through gestation, the ectoderm is differentiated into the neuroectoderm layer of the embryo giving rise to the nervous system and the skin epithelium by day 21 of gestation.18, 22 The initial step of epidermal stratification is usually after week 4 of gestation, the epidermal basal layer (BL) gives rise to the periderm layer. The periderm layer contains endodermis-like cells that protects the developing epidermis from amniotic fluid and manages glucose uptake.1 There are 6 to 8 basal layers for each periderm. However, after week 23 of gestation the periderm is no longer present in the basal layer.16 The next layer of the epidermis that is made is between the basal layer (BL) and the periderm layer which is called the intermediate layer.18 The intermediate layer is associated with the asymmetric cell division/ differentiation of the epidermal basal cells that proceeds through eight stages which occurs between week 5 to week 26 of gestation.
The intermediate layer cells are referred to as keratinocytes and melanocytes. The keratinocytes start undergoing profileration and mature into the spinous layer where the cells are now expressing K1 or K10 from week 8 to week 14 of gestation.9 The keratinocytes in the epidermis are a part of the immune system that aids in the protection against infection and acts as a defense mechanism if the stem cell is breached. Keratinocytes reside in the basal layer because K5 or K14 expression replaced K8 or K18 expression. By week 26 of gestation, keratinocytes are completely formed in the epidermis with one basal layer (BL), 2 to 3 spinous layers (SL), a granular layer (GL), and 5 to 6 stratum corneum layer (CL).16
The complete stratification of the epidermis. While melanocytes are similar to dendritic cells that reside in the basal epidermal layer. The melanocytes appear to express antigens by week 5 to week 8 of gestation. Melanocytes in the epidermis make melanin, which is the pigment in the epidermis that is responsible for skin color. When skin is exposed to sunlight/ ultraviolet radiation, the melanocytes within the epidermis activate and transport melanin to provide a shield to the living epidermis cells to protect DNA damage in living cells. Langerhans cells (LC), also starts to appear and express antigen that are found in the epidermis by week 6 of gestation.6 From week 14 to 17 of gestation the upper spinous cells are flattened now turned into matured spinous cells from the spinous layer (SL) which mature into Involucrin-positive granular layer (GL).
Involucrin is a precursor in the stratum corneum envelope and is also present in the spinous, granular, and stratum corneum layers in the skin. The stratum corneum envelope is insoluble structures that provide the ability to recover from injuries. Involucrin is a ceramide bilayer that is bound to envoplankin and periplankin on the cell surface making the envelope. The last step of epidermis stratification occurs when the cells in the granular layer (GL) terminally differentiate into Filaggrin and Loricrin expressing cornified cells to form the new cornified layer (CL). The major protein in the envelope is Loricrin which is intertwined with small proline-rich proteins to provide the barrier function of the epidermis. Filaggrin comes from the profilaggrim in the keratohylain granules of granular layer forms the stratum corneum keratin filaments which undergoes proteolysis to make the natural moisturizing factor (NMF). NMF is responsible for the stratum corneum to keep its water giving rise to hydration and flexibility in the epidermis.
The cornified cells in the cornified layer form the envelop and fulfills the barrier function of the skin forming the stratum corneum component during the last trimester of gestation.20 At the same time the stratum corneum component forms Vernix appears and serves as a cover for the fetus from head to toe and back to front allowing the stem cell to develop in a wet uterine environment.21 Through gestation, the Wnt pathway plays a highly important role in the regulation and production of the development of skin illustrated in Figure 3. Wnt protein that are secreted will stimulate many intracellular signaling pathways that have the ability to act as a growth factors that causes production of skin, proliferation, differentiation, and polarity. When the Wnt pathway is stimulated by Wnt protein, the Wnt/ß-catenin signaling is utilized in the regulation of this pathway in which aids the stratification of the epidermis during gestation.
Deregulation of Wnt/ß-catenin signaling correlates to several human diseases and cancers.10 Additionally, ß-catenin-independent Wnt signaling, Wnt-activated signaling pathways that do not depend on ß-catenin are known as non-canonical Wnt pathways play a major role in cancer and development of diseases because it has the ability to inhibit Wnt/ß-catenin signaling.15 The Wnt pathway is first activated when a Wnt ligand binds to the receptor or co-receptor. Wnt proteins encoded for a family of genes that are kept in the nucleus of animals. In the animal kingdom there are 19 Wnt genes so far that have been identified in mouse and human genomes.10 Wnt proteins undergo post-translational modifications that include glycosylation and palmitoylation which are very important in Wnt secretion and Wnt binding to receptors.
Synthesized Wnt proteins are glycosylated and palmitoylated in the endoplasmic reticulum by porcupine so the Wnt proteins can be transferred into the Golgi. In the Golgi, Wntless (Wls), a transmembrane protein essential for Wnt secretion.Wls binds to the Wnt proteins and guides the Wnt proteins out of the Golgi to the plasma membrane and then Wnt proteins are released to bind to the target cells in an autocrine or paracrine way.4 However, if Wls contained a mutation, K14-Cre; Wlsfl/fl causing a loss of function in Wls, could result in epidermal differentiation and skin barrier defects because Wls guides the Wnt proteins to bind to specific target cells.3 The newly secreted Wnt proteins serve as Wnt ligands that interact with the receptor complexes made up of Frizzled (Fz) family receptors which recruits co-receptors such as LRP-5/6 (lipoprotein receptor-related protein) that aid in activating the signaling pathways.13, 24 The Wnt ligand binds to the Frizzled and LRP-5/6 forming the receptor and co-receptor complex which recruits the Dishevelled protein (Dvl) causing the inhibition of the degradation complex responsible for degrading ß-catenin resulting in stabilized ß-catenin. If ß-catenin was not stabilized and contained a mutation, En1-Cre; Ctnnb1fl/D caused a loss of function that resulted in reduction profileration of the dermal fibroblast however, if ß-catenin obtained a gain of function mutation it would have the reverse effect that can result in an increase profileration of the dermal fibroblast.
The stabilized ß-catenin accumulates in the cytoplasm and enters the nucleus where it serves as a transcriptional co-activator for the transcription factor family of lymphoid-enhancing factor (LEF) and T-cell factor (TCF) proteins. The way ß-catenin plays a role in being a transcriptional co-activator is by the ß-catenin and LEF/TCF interacting together which encourages transcriptional regulators and histone modifiers which mediates expression of target genes. If LEF contains a mutation such as K14-DNLef1, results in epithelial cysts and development of skin tumors because LEF is very important in encouraging transcription of target genes. Just like LEF, if TCF contains a mutation resulting in a gain of function, epidermis differentiation defects will form; however, if TCF contains a mutation, K14-Cre; Tcf3fl/fl causing a loss of function no epidermal defects occur.23 When the Wnt signaling pathways wants to be deactivated, one of the secreted soluble regulators such as secreted frizzled-related proteins (SFRP), Wnt inhibitory factor (WIF) or Dickkopf proteins (Dkk) blocks the interaction of the Wnt protein and the receptor Wnt is bound to.12 Once one of the secreted soluble regulators are secreted creating the Wnt signal to be conveyed as absent the degradation complex assembles. The degradation complex consists of Axin, casein kinase 1a (CK1a), adenomatous polyposis coli (APC), and glycogen synthase kinase 3ß (GSK3ß).
Phosphorylated ß-catenin is then ubiquitinated by a ß-transducing repeat-containing protein (ß-TrCP) for proteasome-dependent degradation discouraging expression of target genes. If there was a mutation in Dkk, K14-Dkk1 causing Dkk to gain function it would have no effect on epidermis differentiation because Dkk is already inhibiting the Wnt pathway therefore gaining more function would only enhance its normal function. Figure 3. The different types of pathways Wnt can undergo after Wnt secretion produces the Wnt ligand. ß-catenin independent non-canonical are divided into 2 categories: Wnt/Ca21 and Wnt/PCP pathways illustrated in Figure 3.14 In Wnt/PCP pathway the binding of Wnt can bind to either Frizzled or another tyrosine kinase type receptor like Ror2 which can initiate multiple signaling cascades. However, in Wnt/Ca21 pathway, the Wnt receptor and Wnt signaling ligand interact initiates intracellular calcium release causing activation of CaMKII, CaN, or PKC.17Activation of CaN activates the NFAT family proteins for transcriptional regulation involving small GTPases Rho, Rac, and Cdc42 as well as their downstream JNK signaling that regulates cytoskeleton rearrangement and PCP. In summary Wnt plays a very significant role in the gestation and stratification of skin stem cell development. If one of the factors in the Wnt pathway has a mutation that could lead to drastic outcomes such as skin cancer and other diseases.
