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J Anat. 2003 Jan; 202(1): 113–124.
PMCID: PMC1571060

Covering the limb – formation of the integument


An organism's outermost covering, the integument, has evolved to fulfil a diverse range of functions. Skin provides a physical barrier, an environment for immunological surveillance, and also performs a range of sensory, thermoregulatory and biosynthetic functions. Examination of the skin of limb digits reveals a range of skin types including the thickened hairless epidermis of the toe pads (palmar or plantar epidermis) and thinner epidermis between the hair follicles (interfollicular epidermis) of hairy skin. An important developmental function of skin is to give rise to a diverse group of appendages including hair follicles, with associated sebaceous glands (or feathers and scales in chick), eccrine sweat glands and the nail. A key question is how does this morphological variety arise from the single-layered epithelium covering embryonic limb buds? This review will attempt to address this question by linking the extensive morphological/anatomical data on maturation of epidermis and its appendages with (1) current research into the range, plasticity and location of the putative epidermal stems cells; (2) molecular/microenvironmental regulation of epidermal stem cell lineages and lineage choice; and (3) regulation of the differentiation pathways, focusing on differentiation of the interfollicular epidermis.

Keywords: appendages, cell lineages, ectoderm, skin barrier, skin development, terminal differentiation

Epidermis as a structural barrier organ

Normal adult skin comprises a thin surface epidermis nourished and maintained by a thicker dermis. Epidermis of the limb gives rise to a range of skin types (palmar, plantar and interfollicular epidermis) and varied appendages (including hair follicles, sebaceous glands, eccrine sweat glands and the nail) (Fig. 1). Epidermis’ primary role is protective and it provides protection largely through construction of an elaborate and highly organized outer surface, the stratum corneum. Stratum corneum is the primary interface and barrier between an organism and its outer environment and acts to prevent desiccation, toxin entry and microbial infection.

Fig. 1
Section of mouse toe showing a wide range of skin types and variety of appendages. These include thickened hair-less epidermis of the toe pad (palmar or plantar epidermis, pp), interfollicular epidermis (if), dermis (de), hair follicles (hf), sebaceous ...

A key feature of this protective outer layer is that it is continually shed and replenished by underlying keratinocytes, so that damaged, infected or contaminated cells are removed from the body and the barrier is maintained. The stem cells necessary for maintenance of this cycling structure are located in the basal stratum of epidermis (Fig. 2) and in specialized compartments of skin appendages like hair follicles (see reviews by Lavker & Sun, 2000; Fuchs & Raghavan, 2002; Niemann & Watt, 2002; Watt, 2002). Proliferative keratinocytes (transit or transiently amplifying cells) derived from these stem cells also reside in this basal layer (see Fig. 4). In response to various cues, basal keratinocytes withdraw from the cell cycle and are displaced through successive strata to the outer surface of epidermis. With outward migration these keratinocytes change their pattern of gene expression to make the proteins and lipid necessary for formation of the elaborate and complex stratum corneum.

Fig. 2
Diagrammatic representation of adult skin. The basement membrane separates the dermis (primarily consisting of fibroblasts, elastin and collagen) and the overlying epidermis. The epidermis comprises four distinct layers, basal, spinous, granular and the ...
Fig. 4
Models for follicle induction. (A) Follicle spacing may be determined by the ‘reaction-diffusion’ principle (Nagorcka & Mooney, 1985; see text). (i) Pro-follicular molecules (e.g. FGFs, Eda – red) localize to the placode ...

Stratum corneum consists of anucleate, flattened keratinocytes embedded in a lipid matrix (Fig. 2; reviewed by Kalinin et al. 2001). These terminally differentiated keratinocytes (cornified cells or squames) consist of aggregated keratin enclosed by a complex multiprotein cornified envelope which is cross-linked externally to extracellular lipid. The importance of the envelope is demonstrated by neonatal lethality due to barrier function failure in mice null for a key transglutaminase enzyme needed for cross-linking these stratum corneum proteins and lipids (see Fig. 2 inset; Kuramoto et al. 2002).

A complex array of keratinocyte junctions also contribute to barrier function of epidermis either directly or indirectly via regulation of epidermal architecture and keratinocyte proliferation and differentiation. Apical actin-linked tight junctions occur in granular layer keratinocytes (Fig. 2). Transgenic studies, including knockout of an epidermal tight junction protein and misexpression of tight junction components, show that these junctions provide a second tier of barrier protection under the stratum corneum, preventing vertical transmission of substances between epidermal cells (Furuse et al. 2002; Turksen & Troy, 2002; reviewed by Tsuruta et al. 2002). Gap junctions provide intercellular communication between keratinocytes, most prominently during embryogenesis. Mutations in the major gap junction proteins, connexins, are associated with epidermal disease and these proteins display a complex, overlapping expression pattern in adult skin (Di et al. 2001, and references within).

The three-dimensional structure and organization of the epidermal layers is maintained by networks of actin and keratin filaments anchored to cell surface multiprotein adherens junctions and desmosomes distributed throughout the epidermis (Fig. 2). Keratin and desmosomal mutations produce blistering or degenerative phenotypes in epidermis (reviewed by McMillan & Shimizu, 2001; Fuchs & Raghavan, 2002), indicating their structural role. Keratins and intercellular desmosomal cadherin subtypes are distributed throughout the strata and correspond with the differentiation status/stratum level of epidermal keratinocytes. Differential stratum-specific location of desmosomal cadherins may regulate or maintain epidermal organization via differential adhesion between keratinoctyes, in a manner analogous to epithelial cell sorting during neurulation (Runswick et al. 2001). A link between adherens junctions and keratinocyte proliferation has been suggested (Vasioukhin et al. 2001) and functional changes in adherens junctions are linked to cancer (reviewed by Fuchs & Raghavan, 2002).

Finally, interaction between the basal proliferative keratinocytes and basement membrane via hemidesmosomal integrins probably regulates and certainly affects the balance between keratinocyte proliferation and differentiation. Stem cells are postulated to be most adhesive and locate to intense integrin-1-positive areas in the basal keratinoctye layer (Jensen et al. 1999). Cells destined for differentiation must down-regulate their integrin receptors prior to movement/displacement to the surface.

This account stresses the role of epidermis as a physical barrier but this organ also provides a milieu for immunological surveillance via epidermal dendritic cells primed to respond rapidly upon breach of this primary physical barrier (Robert & Kupper, 1999; Jameson et al. 2002; see comment by Schroder in Chuong et al. 2002).

Early embryonic ectoderm

In the post neurula embryo the surface epithelium is a single cell-layered highly proliferative ectoderm (Fig. 3A). An embryonic-specific interface between the embryo and the amniotic fluid is produced by initial stratification. This interface, the periderm (Fig. 3B), will be shed before birth, often in conjunction with formation of the stratum corneum and acquisition of first barrier activity (Hardman et al. 1999). This suggests that with acquisition of postnatal barrier capability periderm becomes redundant. A protective embryonic barrier function of periderm to amniotic fluid is suggested by the presence of periderm-specific tight junctions (Morita et al. 2002). Conversely, blebbing and surface microvilli imply an interactive role for periderm with amniotic fluid (Holbrook & Odland, 1975).

Fig. 3
Epidermal development. (A) Epidermis is derived from single-layered embryonic ectoderm, which undergoes stratification to produce a transitory embryonic cell layer known as the periderm (B). Further stratification of the ectoderm produces an intermediate ...

Barrier activity, conferred by fully differentiated epidermis, is essential by birth when an organism confronts the arid and toxic postnatal environment. However, embryonic integument initially must maintain a high proliferation rate to cope with a rapidly expanding surface area. Adoption of the terminal differentiation programme leads to a rigid stratum corneum and restricts the ability of integument to expand horizontally. This may be why organisms delay adoption of epidermal late terminal differentiation until after body pattern is fully established – in rodents stratum corneum formation is delayed until just before birth (Hardman et al. 1998). It is also possible that the signalling role of embryonic epidermal structures, such as the apical ectodermal ridge, could not be maintained if the epithelium was terminally differentiated. Therefore, subsequent stratification of ectoderm produces another uniquely embryonic layer, the intermediate layer or stratum intermedium (Fig. 3C). Intermediate layer cells are proliferative and express keratins and other marker proteins characteristic of basal keratinocytes (Byrne et al. 1994), differing fundamentally from the suprabasal or spinous layers of postnatal epidermis. This embryonic epidermis is suited to rapid horizontal expansion to provide increased surface area. It is at this stage of development that appendages form in embryonic ectoderm.

Models for appendage and non-appendage epidermal fate

Appendage formation (formation of hair, feathers, scales, nails and glands) involves a change in ectodermal stem cell lineages and there is substantial evidence that this change is programmed by underlying mesenchyme (Sengel, 1990). In postnatal epidermis, stem cells reside in both the basal interfollicular epidermis and within specialized compartments of the appendages (e. g. the bulge region of hair follicles, Cotsarelis et al. 1990; however, see also Panteleyev et al. 2001).

Evidence is accumulating that stem cells from each location have potential to interconvert between lineages, suggesting that epidermal stem cell lineages remain plastic and are programmed by microenvironment (Reynolds & Jahoda, 1992; Ferraris et al. 2000; Taylor et al. 2000; Oshima et al. 2001; Liang & Bickenbach, 2002; reviewed in Jahoda & Reynolds, 2000; Niemann et al. 2002). For example, corneal epithelial cells can be experimentally reprogrammed to follow epidermal appendage differentiation (Ferraris et al. 2000) and epidermal cells can support follicle differentiation (Reynolds & Jahoda, 1992). In hairy skin in vivo it is probable that the interfollicular epidermal lineages are replenished from a reservoir of hair follicle stem cells (Taylor et al. 2000; Oshima et al. 2001).

The relationship between ectodermal stem cells and adult epidermal and appendage stem cells is still unclear; however, early embryonic ectodermal stem cells must be able to follow all possible lineages. In one of the first studies linking embryonic and adult stem cells it was shown that embryonic hair follicle stem cells are located throughout the ectodermal portion of the immature follicle. Their location is then sequentially restricted during follicle development to achieve that characteristic of adult hair follicle stem cells (Akiyama et al. 2000).

The field of epidermal development benefits from a background of extensive epidermal–mesenchymal recombination experiments between tissues from different developmental times, body sites and even species (reviewed in Sengel, 1990; Hardy, 1992). These experiments show that interactions between mesenchyme and ectoderm control appendage formation and determine appendage location and type. Hence, the nails of the limb are probably initiated by mesenchymal signals from the digit tips. The initial morphological signs of appendage formation are aggregation of mesenchymal cells at discrete locations and elongation of ectodermal cells into structures called placodes. Subsequent steps of placodal differentiation differ with appendage type. Appendage formation is best characterized in molecular terms for the feather and hair follicle.

The first signal specifying follicle formation is believed to be mesenchymal and signals to the overlying ectoderm to make an appendage. It is possible that this early signal is not localized to putative placodes but is homogenous and that signalling within overlying ectodermal cells restricts response to the mesenchymal signal to placodal regions (Jung et al. 1998; Noramly & Morgan, 1998; Noramly et al. 1999).

Although the nature of these early signals are still unknown, one of the earliest intercellular ectodermal signalling events is the Tabby/Downless interaction. This involves a TNF-like molecule (ectodysplasin or Eda) and its receptor EdaR which resembles the TNF-receptor (Headon & Overbeek, 1999; Huelsken et al. 2001). Mutations in either component produce defects in hair follicles, teeth and sweat glands associated with the human disorder hypohidrotic ectodermal dysplasia (reviewed in Barsh, 1999; Headon & Overbeek, 1999; Monreal et al. 1999). Other molecular effectors of early follicle formation are fibroblast growth factors (FGFs), bone morphogenic proteins 2 and 4 (BMP2 and 4) and Wnt (mammalian Wingless homologues; reviewed in Oro & Scott, 1998; see below). BMPs and Wnts act downstream of Eda/EdaR (Headon & Overbeek, 1999; Huelsken et al. 2001).

One of the major models for hair follicle formation is based on the ‘reaction-diffusion’ principle (Nagorcka & Mooney, 1985; Fig. 4A). In these models, follicle activators and inhibitors concentrate within the placode, and activators (e.g. Eda, FGFs) are proposed to have limited diffusion capability compared to follicle inihibitors (e.g. BMPs; reviewed by Oro & Scott, 1998; Barsh, 1999; Fig. 4Ai,ii). It is the interaction between activators and inhibitors that determines follicular vs. interfollicular cell fates and determines follicle spacing (Fig. 4Aiii). In this model, the interfollicular fate occurs when effective concentrations of follicular inhibitors outside the placodal region exceed that of activators within the placode. This view implies that the interfollicular differentiation pathway or lineage is a default lineage.

Another model for follicular and interfollicular fates draws on the view that epidermal stem cells are programmed down different lineages (Niemann & Watt, 2002; Fuchs & Raghavan, 2002), i.e. follicular and an interfollicular fate arise from a multipotent ectodermal stem cell (Fig. 4B). There is very strong evidence that activation of Lef1/TCF transcription factors by Wnt family members induces appendage formation (van Genderen et al. 1994; Gat et al. 1998; DasGupta & Fuchs, 1999; Noramly et al. 1999; Widelitz et al. 1999, 2000; Huelsken et al. 2001; Merrill et al. 2001; Niemann et al. 2002). Wnt signalling is involved in early steps of follicle specification, since changes to Wnt signalling (through knockout, ectopic expression, or altered activity of transcriptional activators downstream of the canonical Wnt pathway – Lef1, β-catenin, Tcf-3 (Nusse, 1999) affect early stages of follicle initiation (DasGupta & Fuchs, 1999; Noramly et al. 1999; Widelitz et al. 1999, 2000; Huelsken et al. 2001; Merrill et al. 2001; Niemann et al. 2002).

Most intriguingly, recent experiments involving removal or interference with Wnt signalling produced ‘transdifferentiation’ of follicular cells to epidermal or sebocyte phenotypes, suggesting that this pathway can influence lineages of stem cells (Merrill et al. 2001; Huelsken et al. 2001; DasGupta et al. 2002; Niemann et al. 2002). In addition, experimental stabilization of β-catenin produces transdifferentiation of mammary and other secretory epithelia to an epidermal fate (Gounari et al. 2002). These demonstrations of how a signalling pathway can regulate epidermal stem cell lineages fit a model whereby multipotent stem cells residing in epidermis can follow a range of lineages controlled by signalling pathways specified and modified by microenvironment. It is possible that key factors in microenvironmental regulation of stem cell lineage are the underlying mesenchyme or relative concentrations of activators/inhibitor proposed by the reaction diffusion model (Fig. 4A).

Terminal differentiation of interfollicular epidermis – formation of the barrier

Multilayered, proliferative embryonic ectoderm (Fig. 3C) will enter terminal differentiation to produce a structure that biochemically and functionally resembles adult skin. Regulation of this process during embryogenesis is poorly understood. Assumptions about regulation of embryonic terminal differentiation have been inferred from terminal differentiation in adult skin (reviewed in Dotto, 1999).

Analysis of adult epidermal terminal differentiation takes advantage of keratinocyte culture systems that show controlled terminal differentiation in response to external signals, particularly calcium (Hennings et al. 1980; Yuspa et al. 1989). There is an extracellular calcium gradient in epidermis peaking at the granular layer (Menon & Elias, 1991) and much keratinocyte enzyme activity (e.g. transgluatminase activity) in differentiated layers, and differentiation-specific gene induction is dependent on extracellular calcium levels. Similarly, formation of desmosomal and adherens junctions is also calcium-dependent (Hodivala & Watt, 1994). This calcium gradient can be detected by late gestation (Elias et al. 1998). There is a calcium-sensing receptor in murine epidermis and knockout affects terminal differentiation (Komuves et al. 2002); however, the presence of an alternatively spliced isoform in skin complicates assessment of the importance of this receptor.

Mouse models that arrest at distinct stages of epidermal differentiation are proving particularly informative in dissecting terminal differentiation regulatory pathways. For example, epidermal development in mice null for p63, a p53 homologue expressed in the basal layer of epidermis, arrest at a very early stage of embryonic ectoderm prior to stratification (Fig. 3A; Mills et al. 1999; Yang et al. 1999). This suggests inability of embryonic ectodermal cells to leave the transit-amplifying population (Fig. 4). An explanation of this phenotype is suggested by the finding that p63 induces Jagged-1, a Notch ligand which can activate Notch 1 signalling in adjacent cells (Sasaki et al. 2002). Jagged-1 is prominently expressed in epidermis and Jagged-1 induction of Notch signalling induces cell cycle arrest and terminal differentiation in culture models (Rangarajan et al. 2001; Nickoloff et al. 2002) and mice, partly by induction of the cyclin-dependent kinase inhibitor p21 (Rangarajan et al. 2001). Epidermal-deficient Notch1 mice display a complex phenotype of abnormal terminal differentiation, reflecting additional roles for Notch1 later in terminal differentiation (Rangarajan et al. 2001).

Interaction between Notch1 and its ligand Delta1 is also proposed to regulate entry to the transit-amplifying population. Delta1 associates with stem cell clusters in the basal layer, excluding Notch1-expressing cells, and Notch1-mediated induction of cell cycle arrest occurs at boundaries of Delta1-expressing cells (Lowell & Watt, 2001). This provides some parallels with cell fate choice in Drosophila epidermis.

An example of a mouse model arresting after stratification but before entry into terminal differentiation (Fig. 3C) is the mouse Ikappa kinase (IKK) alpha knockout (Hu et al. 1999; Li et al. 1999; Takeda et al. 1999). Ikkalpha is a subunit of IKappaB kinase which phosphorylates Ikappa B, leading to its degradation and activation (nuclear translocation) of nuclear factor kappa B (NfkappaB). Unexpectedly, the role of IKKalpha in epidermal differentiation is independent of NfkappaB, but acts to induce an, as yet, undefined keratinocyte differentiation factor (Hu et al. 2001; Pasparakis et al. 2002).

Transcription factor Kruppel-like factor 4 (Klf4) null mice provide an example of successful completion of early terminal differentiation but faulty completion of late terminal differentiation (Fig. 3E; Segre et al. 1999). These mice are deficient in production of cornified envelope precursors and lipids necessary for formation of the stratum corneum and die due to barrier defects. A more global example of arrest before late terminal differentiation is provided by ectopic expression of TCF3 in interfollicular epidermis, a site where it is normally absent (Merrill et al. 2001). Ectopic induction of TCF3 downstream genes is proposed to induce a lineage change, so that cells of the upper strata now express keratin markers characteristic of follicle and sebocyte fates. These mice also have barrier defects.

Dermal regulation of interfollicular terminal differentiation

Entry into epidermal terminal differentiation is regulated by mesenchyme during development (Sengel, 1976) though the mechanism is still unknown. In a particularly elegant set of experiments, Szabowski et al. (2000) demonstrated a paracrine interaction between dermal fibroblasts and basal cell keratinocytes that regulate terminal differentiation in adult, directly demonstrating and providing a mechanism for dermal regulation of epidermal differentiation. Bypassing the embryonic lethal phenotype of cJun and Jun-b (AP1 subunits), null mice, a tissue engineered keratinocyte-fibroblast co-culture skin model was used to show that dermal fibroblasts null for AP-1 subunits were deficient in production of FGF 7 (or keratinocyte growth factor, KGF) and granulocyte macrophage colony stimulating factory (GM-CSF) cytokines, necessary for regulating keratinocyte proliferation and differentiation. KGF activity was mitogenic, affecting proliferation of keratinocytes; however, GM-CSF activity affects terminal differentiation. Interestingly, a double paracrine interaction was demonstrated by action of keratinocyte interleukin 1 (IL-1) regulating the expression of AP1 subunits in dermal fibroblasts, hence FGF-7 and GM-CSF production. Levels of cytokines in these experiments influenced epidermal morphology (e.g. epidermal thickness, quality of granular layer), which suggests a route for generation of regional differences in epidermal quality (see Fig. 1) via changes in levels of dermally produced cytokines.

Although the role of FGF7 in epidermis is mitogenic, the closely related FGF10, produced by basal layer keratinocytes, affects late epidermal terminal differentiation characteristics (Suzuki et al. 2000). Knockout of the cognate epidermal receptor, FGFr2-IIIb (Beer et al. 2000), produces animals with thinner terminally differentiated skin but with the gross phenotype of defective barrier (shiny skin; De Moerlooze et al. 2000).

Conclusion – future work

Analysis of epidermal development is drawing heavily from a view of stem cells and their lineages as plastic, interconvertable and influenced by microenvironment (Goodell, 2001). Epithelial–mesenchymal interaction has been emphasized as a regulator of skin development using classical (tissue recombination) approaches and so mesenchyme/dermis may be a significant microenvironmental affector of the various skin lineages. Elucidation of regulators of lineage choice and differentiation is underway.

Embryonic ectoderm is studied by developmental biologists as a morphogenetically active component of organ development and, in its own right, as a precursor of adult skin as a barrier-organ. During limb development epithelial–mesenchymal interaction, which regulates development and differentiation of epidermal types and appendages, is also involved in patterning of the limb, e.g. in formation of dorsal and ventral characteristics, maintenance and signalling from the apical ectodermal ridge. An interesting question is do these characteristics of embryonic ectoderm, which have been interpreted in terms of limb patterning, influence the course of epidermal development? Also, is this demonstrated signalling capacity associated with ectodermal keratinocytes maintained or inducible in adult keratinocyte stem cells, i.e. will research results derived from limb patterning and development integrate with and contribute to the fields of epidermal development and differentiation?


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