Desmosomes in Developing Human Epidermis

Abstract

Desmosomes play important roles in the cell differentiation and morphogenesis of tissues. Studies on animal models have greatly increased our knowledge on epidermal development while reports on human developing skin are rare due to the difficult accessibility to the samples. Although the morphology of periderm cells and the process how the epidermis develops very much resemble each other, the timetable and the final outcome of a mature human epidermis markedly differ from those of murine skin. Even the genetic basis of the junctional components may have profound differences between the species, which might affect the implementation of the data from animal models in human studies. The aim of this review is to focus on the development of human skin with special emphasis on desmosomes. Desmosomal development is mirrored in perspective with other simultaneous events, such as maturation of adherens, tight and gap junctions, and the basement membrane zone.

Full text

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Hindawi Publishing Corporation
Dermatology Research and Practice
Volume 2010, Article ID 698761, 6 pages
doi:10.1155/2010/698761
Review Article
DesmosomesinDeveloping HumanEpidermis
SirkkuPeltonen,1LauraRaiko,1,2andJuha Peltonen2
1Department of Dermatology, University of Turku and Turku University Hospital, PL 52, 20521 Turku, Finland
2Department of Cell Biology and Anatomy, University of Turku, 20520 Turku, Finland
Correspondence should be addressed to Sirkku Peltonen, sirkku.peltonen@utu.fi
Received 1 December 2009; Accepted 2 April 2010
Academic Editor: Eliane J. Mueller
Copyright © 2010 Sirkku Peltonen et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Desmosomes play important roles in the cell differentiation and morphogenesis of tissues. Studies on animal models have
greatly increased our knowledge on epidermal development while reports on human developing skin are rare due to the difficult
accessibility to the samples. Although the morphology of periderm cells and the process how the epidermis develops very much
resemble each other, the timetable and the final outcome of a mature human epidermis markedly differ from those of murine
skin. Even the genetic basis of the junctional components may have profound differences between the species, which might affect
the implementation of the data from animal models in human studies. The aim of this review is to focus on the development of
human skin with special emphasis on desmosomes. Desmosomal development is mirrored in perspective with other simultaneous
events, such as maturation of adherens, tight and gap junctions, and the basement membrane zone.
1.Introduction
The literature on developing human epidermis is limited,
collectively not exceeding 100 cases in the reports covering
the fetal age. The development of human skin has been
studied at the morphological level in quite detail by elec-
tron microscopy [1–3]. The timetable for the formation
of epidermal architecture is based on the evaluation of
sixty human fetuses, age 7–20 weeks [2]. Sparsely located
desmosomes are detected already in the samples from the
youngest fetuses, and during the maturation the density of
desmosomes increases [2, 4].
Since desmosomes are relatively easily identifiable by
their ultrastructural appearance, they were the first spe-
cific cell junctions recognized in human skin by electron
microscopy. The other cell junctions, adherens, tight, and
gapjunctions,wereoriginallyidentifiedandnamedinsimple
epithelia using electron microscopy, but their ultrastructural
characteristics in simple epithelia are not directly applicable
to those of stratified epithelia, such as epidermis. The
recognition of a number of biomarkers of cell junctions
and subsequent availability of specific antibodies at 80’s
and 90’s enabled investigation of the junctional proteins of
epidermis using immunohistochemical approaches at light
and electron microscopic levels. Immunolocalization studies
thus helped the identification of desmosomal, adherens
junction, gap junction and tight junction, components in
developing epidermis. Although some studies regarding reg-
ulation of development of human skin have been published,
very little is known about the regulatory signals regarding
developmental regulation of human skin.
2.Morphological Development of
HumanEpidermis
Humanepidermisisderivedfromasinglelayerofembryonic
surface ectoderm. The ectoderm proliferates in the 4th week
of development and produces two layers of cells [1, 2]
(Figure 1). The inner layer of cells is the basal layer while
the outer layer is called the periderm, and proliferation
takes place in both cell layers [2]. In the 11th week of
EGA, the basal layer produces a new intermediate cell layer
between itself and the periderm which marks the beginning
of stratification and more complicated differentiation of the
epidermis. The periderm cells in contrast, cease dividing in
the first trimester, become larger and elevated, and exhibit
rounded blebs on their outer surfaces [2]. The periderm cells

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Double layered epidermis
Periderm
Basal layer
(a)
(b)
(c)
Periderm
Intermediate
layer
Basal layer
Granular layer
Spinous
layers
Basal layer
Stratifying epidermis
Keratinzing epidermis
Figure 1: Schematic representation of developing human epider-
mis. (a) Two cell layers, peridermal cells and basal cells at the
first trimester (8 weeks). (b) Three cell layers at 11 weeks. The
periderm cells become elevated. (c) By 21–24 weeks all the cell
layers of mature epidermis are present. Tight junctions are shown
inblue,desmosomesinred,adherensjunctionsinyellow,andgreen
indicates gap junctions. The density of junctions increases during
the maturation.
form a cornified cell envelope in the three-layered stage of
development [5, 6]. By 21–24 weeks EGA, the intermediate
cell layer has apparently given rise to the definitive three
layers of the outer epidermis: the spinous, the granular,
and the cornified cell layers. As the keratinization proceeds,
the periderm is gradually shed into the amniotic fluid by
the beginning of the last trimester [3]. The periderm cells
display characteristics consistent with apoptosis prior to
being sloughed off [7]. Cornified cell envelope is formed in
the upper cell layers of epidermis after the shedding of the
periderm cells [5, 6]. Mice and man show clear differences
in the development of the epidermis including the time
schedule, maturity at newborn and differences at the genetic
level. For example, mice posses three dsg1 genes with distinct
epidermal expression patterns whereas there is only a single
human DSG1 gene.
3.Formation of Intercellular Junctions in Early
Two-LayeredEpidermis:4–9 Weeks
Desmosomes are easily detectable in transmission electron
microscopy. Ultrastructural studies have revealed desmo-
somes at 5 weeks of EGA between the basal and periderm
cells [2]. It is possible that desmosomes exist earlier but this
has not been verified because of lack of samples representing
earlier time points. Formation of desmosomes is thus a very
early event well preceding, for example, the maturation of
the basement membrane zone. In the youngest fetal samples
investigated, the desmosomes are widely separated [2] and
evaluation of the electron microscopic images suggests that
the desmosomal plaque is considerably thinner and less
prominent than in later developmental stages, although this
was not highlighted in the original publication.
The protein composition of early fetal desmosomes has
been studied at 5 weeks using serum from pemphigus
patients, but no intercellular fluorescence was detected at
that time [8]. Correspondingly, pemphigus sera revealed
positive immunoreaction only after 11 weeks in the study by
Lane et al. [9]. Thus, the presence of desmogleins could not
be proved in the samples of earliest developmental points
studied. However, at 8 weeks indirect immunofluorescence
with antibodies to desmoplakin, pan-desmocollin, and pan-
desmogleinshowedpunctatelabelingassociatedwithplasma
membranes of peridermal and basal cells [4] (Figures 1 and
2),indicatingthatdevelopingdesmosomeshavetheelements
for transmembrane and plaque parts. The suggestive inter-
mediate filaments binding to the desmosomal plaques in
basal cells are CK5 and CK14 which can be first detected
between8and10weeks[10]whiletheperidermcellscontain
CK19 and CK8 [11].
At eight weeks of EGA, desmosomal proteins were also
localized to the basal plasma membrane of the basal cells
suggesting that separation of cell membranes to basal and
apicolateral compartments had not taken place at this time.
At this time, immunolabeling for β4 integrin shows widely
distributed spots [4], instead of a linear labeling of mature
basement membrane zone. Structural hemidesmosomes are
also not seen in the electron microscopy [2, 12, 13]. These
findings support the view that the polarity of the basal cells
has not developed yet. It is however known that at 5 weeks
EGA, the basement membrane zone is composed of a basal
cell plasma membrane, lamina lucida, and lamina densa [12]
which contain laminin and type IV collagen [9, 14, 15].
β1 integrin can also be seen in the periphery of the basal
cells, including the basal and apicolateral plasma membranes
[4, 16, 17].
In vitro studies on human primary keratinocytes have
shown that adherens junctions precede the development
of desmosomes [18]. Classical cadherins are important
in the initiation of intercellular junction formation, and
regulation of desmosome assembly depends at least to some
extent, on expression of classical cadherins [19], Tinkle et al.
[20]. In two-layered developing human epidermis of eight
weeks, E-cadherin is expressed in the periphery of basal
cells, including the basal aspect, and in the periphery of
peridermal cells. E-cadherin and P-cadherin are also present
in the intercellular junctions of the basal and peridermal
cells [4, 10, 21]. The same localization was also noted for
α catenin, vinculin, and α actinin [4]. This indicates that
the prerequisite for desmosome formation in the form of
adherens junction components is available and thus the
formation of desmosomes may follow the same sequence of
events as has been described in vitro. It should be noted that
theadherensjunctionswerenotreported intheultrastuctural
studies. This is, however, not surprising since the plaque
of the adherens junctions is much less prominent than the
desmosomal plaque and is difficult to visualize even in the
adult epidermis [22].

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Dermatology Research and Practice3
8 wk
Desmoplakin
(a)
11 wk
(b)
21 wk
(c)
NB
(d)
Desmocollin
(e)(f)(g)(h)
Desmoglein
(i)(j) (k)(l)
Figure 2: Expression and localization of desmosomal proteins in developing human skin at 8, 11, and 21 weeks of EGA and at newborn
age (NB). Note the gradual increase in the density of desmosomes. At 8 weeks EGA, the epidermis is composed of basal and peridermal cell
layers (a, e, i). Antibodies to desmoplakin (a), desmocollin (e), and desmoglein (i) label cell membranes of basal and peridermal cells. Note
also immunolabeling in the dermal-epidermal junction. At 11 weeks EGA, the intermediate cell layer has developed in the epidermis (b, f, j).
An intense signal for desmoplakin (b), pan-desmocollin (f), and pan-desmoglein (j) is apparent in the peridermal cells. Intermediate cells
also show desmosomal antigens, while lateral membranes of basal cells are almost devoid of these desmosomal proteins. At 21 weeks EGA,
the peridermal cell layer has been shed and the epidermis is composed of the four definitive layers of epidermis (c, g, k). Desmoplakin (c),
desmocollin (g), and desmoglein (k) antibodies label all the cell layers, the basal cells being only weakly labelled (arrowheads point to the
dermal-epidermal junction; bars (a, e, i) 10μm, (b, c, d, f, g, h, j, k, i) 20μm).
It should also be noted that tight junctions are visible
between the neighboring peridermal cells [23]. Of the
componentsoftightjunctions,ZO-1andoccludin havebeen
demonstrated in the cell junction complexes of peridermal
cells between 8 and 21 weeks of EGA [23]. Tight junctions
are responsible for the epidermal diffusion barrier at this age
when mature stratum corneum does not exist. Providing dif-
fusion barrier for the epidermis might also be an important
basic function of the periderm.
Gap junctions, composed of connexin (Cx) subunits,
arechannelsthatallowintercellularcommunicationbetween
adjacent cells. They are considered to play a key role in the
regulationofcellproliferationanddifferentiation.Themajor
Cx subtypes in human skin are Cx26 and Cx43 [24]. The
first connexin type expressed already at 7 weeks is Cx26 [25]
and sparse gap junctions containing connexin 43 are present
at eight weeks [4]. Formation of gap junctions increases
while the epidermis develops and matures, suggesting that
gap junctions may play an important role in fetal skin
development.
4.Initiationof Stratification and
Differentiationof the Basal Cells
between9 and20 Weeks
Between 9 and 20 weeks, the intermediate filament bun-
dles associated with desmosomes become larger and more
prominent, and the number of desmosomes increases [2,
11]. The new intermediate layer of cells contains more

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desmosomes and more prominent keratin filaments than
the basal and periderm cells. The putative binding partners
for desmosomal plaque proteins are CK5 and CK14 in the
basal cells, while the intermediate cells change the expression
to CK1 and CK10 [11]. As the stratification proceeds, CK1
and CK10 are expressed in all suprabasal cell layers. CK8
and CK19 are still expressed in both the basal and periderm
cell layers at this stage of development, but disappear with
keratinization, by about 24 weeks EGA [11].
When the stratification takes place, labeling of the
basal cells for desmoplakin, pan-desmocollin, and pan-
desmoglein becomes very weak and only some distinct spots
ofdesmosomesarevisiblebetweenthebasalcells[4](Figures
1 and 2). The basal cells have acquired their polarity and
the desmosomal proteins have disappeared from the dermal-
epidermal junction. Both of these characteristics resemble
those of mature epidermis. The intermediate cells express
all the desmosomal proteins studied which is in accordance
with the presence of numerous desmosomes in the mature
spinous cell layers. A study using pemphigus sera suggests
that at this developmental state desmoglein3 is present in the
basal and intermediate layers [9] while the peridermal cells
merely show diffuse cytoplasmic labeling for many proteins
studied [4, 9]. By 21 weeks, EGA the labeling pattern for
desmosome components becomes more continuous which
indicates the presence of more numerous desmosomes at the
cell-cell contacts (Figure 2).
During stratification the expression profiles of adherens
junction proteins undergoes minor changes. The basal cells
continue to express both E- and P-cadherins, while the
intermediate cells express only E-cadherin [21]. The α-
actinin disappears from the peridermal cells already by 11
weeks, while being prominently expressed in the junctions
connecting basal and intermediate cells throughout the
development [4]. α-catenin and vinculin are expressed in all
the three epidermal layers. Between 13 and 21 weeks, as the
number of intermediate cell layers increases, the expression
pattern remains essentially the same and by 21 weeks EGA,
the labeling patterns of adherens junction antigens resemble
that of neonatal epidermis. The expression of β1 integrin
continues in the basal cell layer as described earlier [16, 26].
Simultaneously with the initiation of stratification, the
basement membrane zone goes through major changes
as hemidesmosomes and anchoring fibrils begin to shape
[12, 13]. Between 9 and 15 weeks (EGA), the number of
hemidesmosomes is increased by about fourfold, they are
maturedandbecomeincreasinglyassociatedwithintermedi-
ate and anchoring filaments [9, 14]. By 20 weeks (EGA), the
expression of α6β4 integrin becomes mostly concentrated at
the basal surface of the basal cells [4, 26, 27]. The basement
membrane becomes continuous and thicker.
5.Keratinizationof the Epidermisand
Shedding of the PeridermCellsafter
20 Weeks of EGA
By approximately 21–24 weeks EGA, the intermediate cell
layerhas proliferated and produced the definitive three layers
of the outer epidermis: the spinous, the granular, and the
cornified cell layers [28] (Figure 1). As the keratinization
proceeds, the periderm is gradually shed into the amniotic
fluid [3]. After 20 gestational weeks the morphology of
the epidermis increasingly resembles that of a newborn.
The expression patterns of the cell junction and basement
membranecomponentsremainessentiallythesameandlittle
alterations have been noted during this period of epidermal
development. Desmosomes become more densely located in
the spinous cell and granular cell layers. This is also shown in
theimmunofluorescencelabelingfordesmosomalantibodies
which gradually reveal more continuous pattern in the cell-
cell contacts [4] (Figures 1 and 2). The uppermost granular
cell layer and the lowest layer of the stratum corneum, as
well as the lateral plasma membranes of the granular layer
are interconnected with tight junctions that are intermingled
with numerous desmosomes [23, 29]. The density of gap
junctions increases [4].
6.Regulation of the Development of
HumanEpidermis
Even though some of the signaling molecules and path-
ways are universally conserved, marked differences between
human and mouse exist. Thus, findings in mice are not
directly applicable for human development, or diseases.
Yet, only few reports concerning the regulation of the
differentiation of fetal human skin are available, and selected
ones of those are reviewed here.
Wnt/β cateninsignalingisknowntoplayimportantroles
in the development of skin and its appendages [30]. One
study which was based on five fetal skin samples aged over
20 weeks, showed expression of Wnt3a, active β catenin
and Dkk1 in fetal epidermis [31]. The authors suggest that
Wnt/β catenin, signaling thus plays a role in human fetal
skin development and homeostasis. Further studies would
however be needed in order to investigate this pathway in
more detail and at earlier time points.
Desmosome assembly and disassembly are regulated, for
example, by calcium and cross-talk with adherens junctions
(for review see [32]). Adherens junctions and tight junctions
are also regulated by calcium [33]. The effect of calcium is
at least in part mediated by the epidermal calcium gradient
which results in typical calcium concentrations in different
epidermal cell layers [34]. However, no evidence on the
epidermal calcium levels in fetal skin is available.
The epidermal growth factor (EGF) family comprises
multiple mediators such as transforming growth factor
α, amphiregulin, heparin binding-EGF, and epiregulin,
which are crucially involved in the tissue-specific prolifer-
ation/differentiation homeostasis [35]. TGFα is believed to
play a role in cell proliferation and differentiation via an
autocrine mechanism. It exerts its effects on cells through
binding to the epidermal growth factor receptor (EGFR)
[35]. TGFα has showed a vertical progressive increase in
expression in the fetal skin of 14, 20, and 34 weeks [36].
In contrast to normal adult human skin in which the
EGFR is primarily restricted to the basal and immediately

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Dermatology Research and Practice5
suprabasal keratinocytes, the fetal epidermis showed a
persistent expression of EGFR in all cell layers [37]. Based
on these observations it has been suggested that TGFα and
EGFR interact strictly to promote skin development during
fetal period.
Periderm is an embryonic- and fetal-specific transient
cell layer which is destined to detach into the amniotic
fluid. During human skin development periderm cells and
incompletely keratinized cells are replaced by differentiating
keratinocytes. The fate of the peridermal cells has been
shown to take place via apoptosis [7]. Immunohistochemical
localization of transglutaminases in fetal periderm and inter-
mediate epidermal cells coincides with DNA fragmentation
indicating that apoptosis is involved in deletion of these
stage-specificcells.Thedetachmentofperidermcellsalsohas
to involve disassembly of the desmosomes.
7.Conclusions
Studies on human skin are needed to relate the findings
of animal studies with human development, physiology,
and pathological conditions. Detailed timetables of the
expression of several cell junction components are available,
and based on these studies it is likely that the development
of desmosomes is synchronized with the maturation of other
junction types. However, studies on even the most profound
mechanismsofdifferentiationofhumanskinarestilllacking.
Abbreviations
EGA: Estimated gestational age = the time from
fertilization
EGF: Epidermal growth factor
TNF: tumor necrosis factor.
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