The epidermis is the multilayered stratified epithelium that forms the outermost layer of the skin and protects the body from dehydration, trauma and infection. Embryonic epidermal development is a multi-stage process, commencing with the formation of a single layer of basal keratinocytes derived from the surface ectoderm. Upon detachment from the basement membrane, basal keratinocytes enter a program of terminal differentiation called stratification, which is a stepwise formation of suprabasal epidermal layers characterized by expression of specific keratins at each stage. While surface ectoderm cells express Krt8 and Krt18, basal keratinocytes express Krt5 and Krt14. At approximately E9.5, the first non-basal layer called the periderm is formed. The periderm is a temporary structure that serves as the first barrier to the embryo's physical environment. It exists throughout the entire stratification process and sheds off at approximately E17, when it is replaced by corneocytes. The intermediate cells layer is formed at E14.5 between the basal keratinocytes and the periderm and is the first differentiated suprabasal layer of the embryonic epidermis. The cells constituting the intermediate layer initially proliferate, but then lose their proliferative potential and differentiate into spinous keratinocytes. Spinous keratinocytes, as well as the subsequent granular keratinocytes, express Krt1 and Krt10, which promote formation of desmosome junctions. Development of the spinous and granulous epidermal layers marks the formation of the stratified epidermis and enables the establishment of the outer cornified layer of the skin.
The cornified layer is produced by terminal differentiation of granular keratinocytes into corneocytes and their subsequent death. This highly regulated cell death process is known as cornification and differs from apoptosis. It is characterized by replacement of cellular organelles by a compact protein skeleton, formation of a cornified envelope at the cell periphery and formation of a continuous functional layer of biologically dead corneocytes.
The main characteristic of the granular layer is the presence of keratohyaline granules containing proteins necessary for formation of the cornified layer. Filaggrin, produced by proteolytic cleavage from its precursor form, profilaggrin, is the major component of the granules of upper layer granular keratinocytes and corneocytes. Cornification is driven by transglutaminases that crosslink intracellular filaggrin, involucrin and loricrin, as well as the keratin filaments adjacent to the cell membrane. The resulting cornified envelope is formed at the cytoplasmic side of corneocytes and is crosslinked to the corneodesmosomes connecting corneocytes. In addition, intracelullular lipid lamellae, produced by lamellar bodies in granular keratinoyctes and corneocytes, are extruded through the cell membrane and release lipids and desquamating enzymes into the intercorneocytic space. There, the lipids promote formation of the highly hydrophobic extracellular lipid matrix, which regulates water permeability, while the enzymes lead to degradation of corneodesmosomes and shedding of the cells at the skin surface. By E18.5, a mature cornified layer replaces the periderm. The cells in the cornified layer are constantly renewed and shed off the surface as a result of continuous differentiation of the underlying spinous layer.
p63, encoded by the Trp63 gene, is the master regulator of skin formation. Alterations in the p63 pathway underlie a number of ectodermal dysplasias, developmental syndromes in which the skin and its appendages do not develop normally. Two main isoforms encoded by Trp63 are TAp63 and ∆Np63, while TAp63 accounts for only 1% of p63 expression during epidermal stratification. Despite efforts to reveal the roles of the two most prevalent p63 isoforms, the specific role of TAp63 is still under debate. However, a knockout mouse model demonstrated that ∆Np63 is indispensable to epidermal differentiation. p63 is already induced in surface ectoderm cells and is responsible for their commitment to the epidermal fate. When basal keratinocytes form, ∆Np63 is expressed and regulates maintenance of the basal layer keratinocytes and their proliferation potential. In intermediate keratinocytes, ∆Np63 regulates cell proliferation, cell cycle and at later stages, enables terminal differentiation and formation of the spinal and granular layers.
The epidermis is the multilayered stratified epithelium that is separated from the underlying dermis by the basement membrane formed by proteins secreted from both dermal and epidermal cells. The epidermis and the dermis function together to promote formation of skin appendages such as hair follicles, nails and mammary glands. The epidermis is continuously regenerated by mitotically active basal keratinocytes that are located in the basement membrane.