Introduction

Development of the human embryo is a complex process involving highly orchestrated cell movements, proliferation, death, and differentiation. This chapter focuses on key events and regulatory mechanisms that result in skin morphogenesis, maintenance, and regeneration. The spectrum of cutaneous abnormalities that can result from mutations in genes with critical roles in skin development is discussed. Ultimately, improved understanding of the pathways and signaling cascades that are disrupted in genetic skin disorders will aid in the development of therapeutic approaches for patients with acquired as well as inherited skin disorders.

Embryonic Origin of the Skin

The skin is composed of diverse cell types of both ectodermal (e.g. keratinocytes, melanocytes, Merkel cells, neurons) and mesodermal (e.g. fibroblasts, hematopoietic cells such as Langerhans cells, endothelial cells) lineages. To understand the origins of these cells, it is important to review the early stages of embryogenesis. Immediately after fertilization, cells divide rapidly, and by the end of the first week, the embryo begins to implant into the uterine wall. During the third week, the embryo undergoes gastrulation, a complex process resulting in the formation of the three embryonic germ layers: endoderm, mesoderm, and ectoderm.

During the next stage of embryogenesis, ectodermal cells commit to either a surface ectodermal or neuroectodermal fate. The surface ectodermal cells eventually differentiate into the keratinocytes of the embryonic epidermis, whereas the neuroectodermal cells invaginate to create the neural tube in a process called neurulation. As the neural tube forms, cells in its dorsal portion separate to form the neural crest. An important neural crest-derived cell in the skin is the melanocyte. Although Merkel cells were once believed to be neural crest derivatives, it has now been established that they descend from the epidermal lineage. The lineage of the dermis depends on the body site. The dermis (and other mesenchymal structures) of the face and frontal scalp are derived from the neural crest, whereas the dermis elsewhere is derived from the mesoderm. Knowing from which germ layer and lineage different cell types in the skin derive helps one to understand the pathophysiology of cutaneous disorders such as Waardenburg syndrome in which craniofacial dysmorphism and hearing impairment as well as pigmentary abnormalities reflect disrupted migration and survival of neural crest-derived cells.

An overview of key events in the development of skin and its specialized structures is shown in Fig. 2.1 .

Critical events in the development of the skin and its specialized structures.

The timeline indicates the time of initiation defined by estimated gestational age (EGA) and duration of pregnancy (by last menstrual period [LMP]). Refers to skin on the back unless otherwise noted.

Epidermal Development

The ectoderm that covers the developing embryo after gastrulation is a single-layered epithelium ( Fig. 2.2A ). The first step in epidermal development occurs when cells of the surface ectoderm adopt an epidermal fate . Although this process does not result in major morphologic changes, it is marked by dramatic alterations in gene expression that result in the formation of the embryonic epidermis, which initially consists of a simple epithelium ( Fig. 2.2B ). Primitive keratinocytes subsequently generate cells of the periderm, a single cell layer that covers the developing epidermis until the cornified cell layer is formed ( Figs 2.2C–F & 2.3A,B ). The periderm is believed to exchange substances across fetal skin and to protect the developing epidermis from forming interepithelial adhesions.

Development of the epidermis.

A The epidermis develops from the surface ectoderm, a single-layered epithelium that initially covers the developing embryo. B Through changes in gene expression, cells of the surface ectoderm adopt an epidermal fate. C Epidermal cells subsequently give rise to the periderm, a cell layer that covers the developing epidermis until cornification occurs. D Epidermal stratification begins with the formation of a highly proliferative intermediate layer between the basal layer and the periderm. E The intermediate layer becomes several cells thick over the next few weeks. F Intermediate cells ultimately withdraw from the cell cycle and differentiate into spinous and granular keratinocytes. G The periderm is replaced by the cornified cell layer.

Development of the skin.

A At 36 days’ estimated gestational age, the embryonic epidermis consists of two layers – a superficial periderm layer overlying a basal layer. B By 72 days, the basal layer has given rise to the highly proliferative intermediate cell layer. C A distinct granular cell layer and stratum corneum are seen in neonatal skin. D An early peg-stage follicle from a mid second trimester fetus. The more superficial bulge consists of the developing sebaceous gland (arrowhead), whereas the deeper bulge represents the insertion point of the future arrector pili muscle and the location of the presumptive follicular stem cells (arrow).

Photomicrographs, courtesy, Dr Karen Holbrook, from Loomis CA, Koss T, Chu D. Fetal skin development. In: Eichenfield LF, Frieden IJ (eds). Textbook of Neonatal Dermatology, 3 ^rd edn. Elsevier, 2014:2–5.

The embryonic epidermis begins to stratify at approximately 8 weeks’ estimated gestational age (EGA) . At this time, basic organogenesis is complete and bone marrow hematopoiesis commences, marking the transition from embryo to fetus. Of note, expression of TP63 is required for epidermal stratification. During the first stage of stratification, an intermediate cell layer is formed between the basal layer and periderm (see Figs 2.2D & 2.3B ). Unlike suprabasal keratinocytes in the postnatal epidermis, the intermediate layer consists of actively proliferating cells. As a consequence, it is able to expand to accommodate the rapid growth of the embryo as well as create additional layers of intermediate cells over the next several weeks (see Fig. 2.2E ). However, the intermediate cell layer is ultimately replaced by post-mitotic keratinocytes undergoing terminal differentiation.

Terminal differentiation, the process resulting in the formation of mature keratinizing epidermal cells, begins during the second trimester. Early cornification can be observed within the hair canal at approximately 15 weeks’ EGA , but it does not commence in the interfollicular epidermis until 22–24 weeks’ EGA, occurring first in the skin on the head, palms, and soles. The process begins when cells in the intermediate layer permanently withdraw from the cell cycle and differentiate into spinous and granular cells (see Fig. 2.2F ). The cornified cell layer, which is composed of “dead” keratinocytes (corneocytes) held together by a matrix of proteins and lipids (see Chs 56 & 124), subsequently starts to form and is several cells thick by 24–26 weeks’ EGA. The corneocytes are a reflection of the closely regulated process of terminal differentiation that is required for normal functioning of the skin. At the time of keratinization, the periderm detaches from the underlying epidermis and is sloughed off into the amniotic fluid, with remnants contributing to the vernix caseosa that coats newborns. During the third trimester, the number of keratohyalin and lamellar granules as well as stratum corneum layers increases. By the mid third trimester, the epidermis is morphologically similar to adult skin ( Figs 2.2G & 2.3C ), although it does not acquire full barrier function until a few weeks after birth.

Development of Specialized Cells Within the Epidermis

Two populations of non-keratinocyte cells – melanocytes and Langerhans cells – migrate to the epidermis during early embryonic development. Melanocytes are derived from the neural crest that forms along the dorsal neural tube. Melanocyte precursors migrate away from the neural tube within the mesenchyme beneath the primitive epidermis. They follow a characteristic trajectory, moving dorsolaterally and then ventrally around the trunk to the ventral midline, anteriorly over the scalp and face, and distally along the extremities. Cutaneous melanocytes also arise from Schwann cell/melanocyte precursor cells that migrate along nerves to the skin via a distinct ventral pathway .

Melanocytes can be identified within the epidermis at approximately 50 days’ EGA based on HMB45 immunostaining and their dendritic morphology. Epidermal melanocyte density is high early in embryonic development (~1000 cells/mm ² ), and it increases further (~3000 cells/mm ² ) as the epidermis stratifies (80–90 days’ EGA) and the appendages begin to develop; later in gestation, the density decreases and becomes similar to that of young adults (800–1500 cells/mm ² ). However, epidermal melanin production does not begin until 3–4 months’ EGA, and melanosome transfer to keratinocytes is not seen until 5 months’ EGA. Even though all melanocytes are functional and in place at birth, the pigmentation of the skin increases over the first few months of life; this process is most pronounced in infants with darker skin phototypes.

Active melanocytes are also present throughout the dermis during embryonic development. Eventually, most of these dermal melanocytes migrate to the epidermis or undergo apoptosis. By the time of birth, dermal melanocytes have generally disappeared, with the exception of certain anatomic sites (head and neck, dorsal aspects of the distal extremities, and sacrococcygeal area), which correspond to the most common locations for dermal melanocytoses and blue nevi (see Ch. 112 ).

Langerhans cell precursors appear within the epidermis during the first trimester and are detectable as early as 40 days’ EGA. These cells can be distinguished by their characteristic dendritic morphology; expression of CD45, HLA-DR, and CD1c; and high levels of ATPase activity. CD1a, Langerin, and Birbeck granules are expressed by 13 weeks’ EGA. The density of Langerhans cells in fetal skin remains low early in gestation and increases to typical adult levels during the third trimester.

Merkel cells , highly innervated neuroendocrine cells involved in mechanoreception, are initially identified within the epidermis during the first trimester. These cells are detected as early as 8–12 weeks’ EGA in palmoplantar epidermis, and slightly later in interfollicular skin. Merkel cells are identified by the presence of cytoplasmic dense core granules and the expression of cytokeratin 20 and neuropeptides. These cells are found in the basal layer of the epidermis, are often associated with appendages and nerve fibers, and are particularly dense on volar skin. The developmental origin of Merkel cells has been the subject of longstanding controversy, but genetic fate mapping studies have demonstrated that mammalian Merkel cells are derived from an epidermal rather than neural crest lineage .