Embryology, Epidermis

Article Author:
Daniel Schlessinger
Article Author:
Amandeep Goyal
Article Author:
Shehla Yasin Belgam Syed
Article Editor:
Sidharth Sonthalia
3/29/2020 6:56:12 PM
PubMed Link:
Embryology, Epidermis


The epidermis is the outermost layer of skin. Its proper development during the fetal period is crucial as a barrier against infections and water loss.[1][2][3]


The epidermis begins developing from the surface ectoderm at the end of the fourth week of life as the neural tube separates from the overlying ectoderm to mark the completion of neurulation. Although after the first few weeks of embryogenesis the epidermis is composed of five strata or layers, during the first few weeks it is composed solely of a basal layer of cuboidal cells lying atop mesenchyme or future dermis. By the fifth week, a secondary layer of squamous, non-keratinizing, cuboidal cells, known as periderm or epitrichium, develops atop the basal layer. By cycling through phases of keratinization and desquamation, the periderm generates a white, waxy substance called vernix caseosa (cheesy varnish), which serves to protect the fetus from amniotic fluid and, as it later exits the birth canal, from bacterial and environmental insults.

The basal layer develops into the stratum germinativum, which proliferates to form a multilayered intermediate zone by the 11th week. By the 20th week, the stratum germinativum begins proliferation and differentiation to form four more superficial strata of epidermis: spinosum (spinous), granulosum (granular; found on the palms of the hands and soles of the feet), lucidum (clear), and corneum (horny). Proliferation between weeks ten and 17 forms epidermal ridges which protrude as troughs into the developing dermis beneath. Deep in the epidermis, lateral plate-derived mesenchymal cells proliferate to form dermis, which fills the space between the epidermal ridges with dermal papillae. Neurovascular supply within the papillae is complete by the end of the first trimester. Between the ninth and 12th weeks, some of the stratum germinativum also differentiates into the first appearance of hair follicles, and by the 12th week, lanugo (fine, soft, unpigmented hair) is visible on the eyebrows, upper lip, and chin. By the seventeenth week, lanugo is substantial and aids in the adherence of the vernix caseosa to the skin. As melanocytes migrate in greater numbers within the epidermis, they also provide pigment to hair bulbs. Ultraviolet light first encountered at birth results in increased amounts of melanin production.

Adnexal structures also develop from the epidermis:

  • Sebaceous glands, which develop from buds of epidermal root sheaths of the hair follicles.
  • Eccrine sweat glands and ducts, which develop from buds of stratum germinativum that migrate into the dermis. A lumen allowing for the egress of sweat contents is then formed as the overlying epidermal layers degenerate linearly.
  • Apocrine sweat glands, which develop from outgrowths of the hair bulbs.
  • Arrector muscles of the hair, which develop from mesenchyme surrounding the hair follicles and attach to their respective dermal root sheaths.

Nails begin development in the ten weeks, when the epidermis at the tips of the digits first thickens, migrates dorsally, and finally keratinizes while growing toward the distal end of the nail plate. This process is complete by the 32 weeks in the fingers and by the 36 weeks in the toes.

Clinical Significance

As the epidermis develops in the first four months, some neural crest cells migrate superficially to become melanocytes, interposed within the epidermal strata. The theoretical paths of dorsal melanocytes, migrating laterally from the midline but stretched by the flexed fetus, is one potential basis for lines of normal cell development called Blaschko's lines. The lines appear V-shaped on the back, S-shaped on the chest, hourglass-shaped on the face, and swirled on the scalp. Certain autosomal and X-linked inherited skin conditions are affecting keratinocytes and melanocytes, such as epidermal naevus, incontinent pigmenti, and lichen planus, tend to follow a Blaschkoid distribution as a visible manifestation of genetic mosaicism. In women, some X-linked disorders follow a Blaschkoid distribution as a result of normal X-inactivation (lyonization) resulting in functional cutaneous mosaicism; one example is X-linked hypohidrotic ectodermal dysplasia. Interestingly, the implicated gene in X-linked ichthyosis, which encodes steroid sulfatase, is known to “escape” X-inactivation and therefore does not follow Blaschko’s lines.[4][5][6][7]

On the soles of the palms and feet, the surface changes resulting from the formation of epidermal ridges are the basis for fingerprints and are determined genetically. Certain genetic diseases, such as Down syndrome, often affect ridge pattern formation, resulting in distinctive phenotypes which can aid in diagnosis.

Several subtypes of ectodermal dysplasia are thought to result from mutations in p63, of the p53 family of transcription factors, which is first expressed at week 8.5 of embryogenesis and appears to play a key role in epidermal stratification. It is thought to exert its effects via maintenance of the epidermal stem cell population and basal layer. Homozygous knockout mice for the p63 gene are born with a single-cell-thick layer of skin rather than a recognizable epidermis, and consequently, expire secondary to dehydration. The phenotype was similar enough to subtypes of congenital ectodermal dysplasia that researchers sought a connection. Indeed, there is a subgroup of ectodermal dysplasia which is linked to p63 mutations; they are inherited in an autosomal dominant fashion and are principally characterized by ectodermal dysplasia, orofacial clefting, and limb malformations.

The embryonic growth and patterning of epidermal stem cells, hair follicles, and sebaceous glands are partially regulated by the molecular signals of the Hedgehog pathways, including the sonic hedgehog (Shh), Indian hedgehog (Ihh), and Desert hedgehog (Dhh) pathways. These pathways are most active during embryogenesis, but they also play a role in postnatal hair follicle growth and epidermal stem cell replenishment. As basal cell carcinoma appears to arise from immature pluripotential cells associated with the hair follicle, it is not surprising that most sporadic basal cell carcinomas contain mutations in the Hedgehog pathways. Inactivating mutations in PATCHED (PTCH), a tumor suppressor in the Shh pathway, are most common. Another 10-20% is caused by activating mutations of smoothened (Smo), the proto-oncogene which PTCH normally represses. Additionally, Nevoid Basal Cell Carcinoma Syndrome (NBBCS, Gorlin syndrome), which is characterized by the development of extracutaneous tumors, skeletal and dermatologic anomalies, and dozens to hundreds of BCCs by early adulthood, is nearly always caused by PTCH mutations. Orally active small-molecule inhibitors of the Shh pathway, such as vismodegib and sonidegib, have demonstrated clinical efficacy in the treatment of locally advanced or metastatic basal cell carcinoma and NBCCS.[8][9]


[1] Suhail S,Sardashti N,Jaiswal D,Rudraiah S,Misra M,Kumbar SG, Engineered Skin Tissue Equivalents for Product Evaluation and Therapeutic Applications. Biotechnology journal. 2019 Apr 12;     [PubMed PMID: 30977574]
[2] Maranduca MA,Branisteanu D,Serban DN,Branisteanu DC,Stoleriu G,Manolache N,Serban IL, Synthesis and physiological implications of melanic pigments. Oncology letters. 2019 May;     [PubMed PMID: 30944614]
[3] Yang WK,Chien CT, Beyond being innervated: the epidermis actively shapes sensory dendritic patterning. Open biology. 2019 Mar 29;     [PubMed PMID: 30914004]
[4] Wang S,Zhang Z,Peng H,Zeng K, Recent advances on the roles of epidermal growth factor receptor in psoriasis. American journal of translational research. 2019;     [PubMed PMID: 30899359]
[5] Luxenburg C,Zaidel-Bar R, From cell shape to cell fate via the cytoskeleton - Insights from the epidermis. Experimental cell research. 2019 May 15;     [PubMed PMID: 30872138]
[6] Bonifant H,Holloway S, A review of the effects of ageing on skin integrity and wound healing. British journal of community nursing. 2019 Mar 1;     [PubMed PMID: 30817191]
[7] Goleva E,Berdyshev E,Leung DY, Epithelial barrier repair and prevention of allergy. The Journal of clinical investigation. 2019 Apr 1;     [PubMed PMID: 30776025]
[8] Hariri H,Kurban M,Al-Haddad C,Fahed AC,Poladian S,Khalil A,Abbas O,Arabi M,Bitar F,Nemer G, Degenerated hair follicle cells and partial loss of sebaceous and eccrine glands in a familial case of axenfeld-rieger syndrome: An emerging role for the FOXC1/NFATC1 genetic axis. Journal of dermatological science. 2018 Dec;     [PubMed PMID: 30514661]
[9] Nguyen MB,Cohen I,Kumar V,Xu Z,Bar C,Dauber-Decker KL,Tsai PC,Marangoni P,Klein OD,Hsu YC,Chen T,Mikkola ML,Ezhkova E, FGF signalling controls the specification of hair placode-derived SOX9 positive progenitors to Merkel cells. Nature communications. 2018 Jun 13;     [PubMed PMID: 29899403]