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An Exploration of the Development and

Morphogenesis of Skin
The role of the skin and its basic structure
This report will investigate the development of the integumental system (skin). The
integumental system is a major system of the body with two main functions: to act as a
barrier and a major sensory organ to the outside environment. The skin also functions
in immune response, thermoregulation, metabolism, endocrine and exocrine pathways,
fluid and electrolyte balance, communication and depending on the species, also
respiration, locomotion and rearing young (Chuong et. al, 2002 and Mancini, 2004).
A mouse embryo of approximately 4-5 days old was predominantly used for assessing
the histology of the integumental system (Figure 1), though this report will consider
the role of skin in all organisms. The integumental system has two major layers: the
epidermis, a stratified squamous epithelial tissue, and the dermis, a dense irregular
connective tissue, as Figure 2 shows. Being an epithelial tissue, the epidermis rests on
a basal lamina, separating it from the dermis. Each layer contains different cells and
therefore different functions and influences the other in select ways. Examples of
cells within the epidermis include: keratinocytes, cells that produce keratin and whose
death forms the outer cornified layer of the epidermis; melanocytes, neural-crest
derived cells that produce melanin which gives the skin its pigmentation; Langerhans
cells, bone-marrow derived granulated dendritic immune cells that engulf microbial
pathogens; epithelial stem cells (progenitors), located in the basal epidermis; hair
follicle cells; and sebaceous gland cells (sebocytes). The dermis contains fibroblasts,
mesenchymal cells that synthesise the fibres and sugar-based molecules of the dermis;
adipocytes, fat-containing cells; macrophages, immune cells which engulf microbial
pathogens; endothelial cells, the cells that line blood vessels; neural cells; stem cells,
some located in the dermal papilla; and other progenitors of neural and endothelial
cells. Stem cells, progenitors and fibroblasts are not terminally differentiated, and can
give rise to many other cells, while the rest of the cells are in some form of terminal
differentiation, the keratinised cells of the epidermis being a good example. The
dermis also contains other fibrous and extracellular components, such as collagen
fibres, elastin fibres, proteoglycans, hyaluronic acid and glycoproteins all suspended in
fluid, the extra-cellular matrix (Brouard & Barrandon, 2003).

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E
A

G
D

B
F
C

Figure 1: Enlargement of the post-natal mouse transverse thoracic section. The location of various organs, tissues
and structures within the section, including A- the spinal cord, B- the lungs, C- the heart (encompassing a large
portion of the thoracic mediastinum), D- the oesophagus, E- the musclular thoracic wall, F- the aorta, G- a
vertebra, as well as H- the skin, are re adily seen.

Epidermis

E
B
C
Dermis

Figure 2: Epidermal and dermal skin layers: The layers of the epidermis, a stratified squamous epithelium, - AStratum Corneum, B- Stratum Lucidum, C- Stratum Granulosum, D- Stratum Mucosum/stratum spinosum and
E- Stratum Germinativum- are distinguishable in the figure. The connective tissue dermis, a dense irregular
connective tissue, is also present with various hair shafts (F).

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From the beginning: zygote to gastrulation

Figure 3: Gastrulation leads to three germ layers

that
Figure
3: give rise to all tissues and organs of the body. The epiblast
of the bilaminar disc gives rise to all of the tissues of the embryo, including the skin. The three germ layers- the
ectoderm, mesoderm and endoderm arise from the epiblast. The ectoderm and mesoderm give rise to cells that
form the skin, the epidermis being derived from the ectoderm and the dermis derived from the mesoderm. This
figure also lists many molecular signals that influence cellular development, including WNT, BMP, FGF and SHH
(Taken from Loebel et al, 2003).

Skin begins its development, like all tissues and organs of the body, back in the newly
fertilised egg, the zygote. The zygote undergoes progressive divisions, generally
dividing symmetrically during early divisions. In fact, at the twelve-cell stage,
generalised cells (blastomeres) fated to develop into the epidermis (and other tissues)
can be traced to four cells of this twelve-cell ball, called ABarp, ABpla, ABpra and C,
respectively (Chisholm & Hardin, 2005). Just prior to hatching and implantation of
the embryo the cells undergo asymmetric division, forming a ball of cells (the
blastocyst) that contains a fluid-filled space, the blastocoel. An important feature of
this stage is a group of cells above the blastocoel collectively known as the inner cell
mass (ICM). These are the cells that give rise to the entire embryo, including the skin
cells. It is here that our major discussion of the development of the skin begins. As
the blastocyst develops even further, the cells of the ICM form two sheets of cells,
with an intervening space. The top sheet, the epiblast, gives rise to the three germ
layers of the embryo- ectoderm, mesoderm and endoderm. Some epiblast cells
migrate through a groove to form a middle layer, which becomes the mesoderm.

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Others implant into the bottom sheet of cells, these are the cells which become the
endoderm. In general, the epidermis of the skin develops from the ectoderm, while the
dermis develops from the mesoderm, see Figure 3. This entire period of developing
the three germ layers is called gastrulation (Loebel et. al, 2003 and Mancini, 2004).
Figure 3 also shows many molecular signals required to differentiate cells into
different lineages. Bone morphogenic protein (BMP) and the Wnt group of signals are
important to differentiate ectoderm from mesoderm. From here on, the development
of the epidermis and dermis is different and will be discussed separately.
The epidermis: an ectodermally-derived epithelial tissue
The epidermis is a stratified squamous epithelium, containing stem cells,
keratinocytes, keratinised cells, melanocytes, Merkels discs, T lymphocytes and
Langerhans cells. The epidermis is derived from ectoderm. As Figure 2 shows, the
epidermis is divided into five layers of cells: the stratum corneum, the outer most layer
of cells that contains keratinised (cornified) dead epithelial cells; the stratum lucidum,
a transparent layer beneath the stratum corneum that contains dead keratinocytes; the
stratum granulosum, so named because of the granulated appearance of the
keratinocytes that are present; the stratum spinosum/stratum mucosum, the layer of
spinous keratinocytes that contain desomsomal junctions between cells and have just
begun keratinisation; and finally the stratum gernivativum/stratum basale, the
innermost layer of cells that are the stem cells of the epidermis, dividing to provide
progenitors that then migrate towards the surface of the epidermis (Brouard &
Barrandon, 2003 and Koster, 2010).
Development of the epidermis

Having discussed the gross structure of the epidermis, its development will now be
explored. From gastrulation, a single-layered surface structure forms from the
ectoderm. This will give rise to the nervous system and the epidermis. These two
fates are regulated by Wnt signalling. Specifically, Wnt signalling prevents the action
of Fibroblast Growth Factors (FGFs), resulting in ectoderm expressing Bone
Morphogenic Proteins (BMPs) instead. The expression of BMPs in ectoderm results
in epidermis, while the expression of FGFs results in neural tissue, as illustrated in
Figure 3. Development of the epidermis also has involvement from a substrate of
neuroblasts. A critical point in the development of the ventral neuroblasts is the
closure of the ventral cleft and migration of the neuroblasts towards the midline from
the lateral portions of the embryo. This step is important because it creates a uniform
layer of neuroblasts, which may be a requirement for further development of the
overlying epidermal cells, specifically in allowing epidermal cells to enclose the
embryo in a single layer of epidermis (Chisholm & Hardin, 2005). Exactly how this
movement occurs and is regulated is unknown. This needs further research.
However, it is known that most movement (and by extension tissue morphogenesis) of
cells requires the action of cytoskeleton remodelling, cell-cell or cell-ECM
interactions and cell polarity (Zhang et. al, 2010). It is also known that the

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commitment of cells to an epidermal fate requires the action of p63 (Koster & Roop,
2007). The resulting ventral and dorsal epidermal sheets contain a single layer of
multipotential epithelial stem cells, covered by a thin layer of protective cells
collectively called the periderm (Fuchs, 2007). We will consider the commitment of
precursor cells to epidermal cells (specification), the enclosure of these two layers and
the stratification of the epidermis in following sections.
Epidermal specification

Upon forming a layer of precursor epithelial stem cells, those stem cells must
differentiate to form cells that are fated to become epidermis. Otherwise cells which
become other tissues, such as neural tissue, would result. This is mediated by the
underlying dermis, though the specific molecular signal involved is unknown. This
provides a good example of an epithelio-mesenchymal interaction. The specific
pathways vary from species to species, but it is clear that Wnt and BMP signalling are
important signalling pathways for epidermal specification (Ohtola et. al, 2008). Also,
p63 is an important transcriptional factor, in fact the first that is specific for epidermal
specification in vertebrates. Without p63, stratification does not occur and mice born
with this null mutation die quickly from dehydration. p63 is also important in further
steps of stratification (Koster & Roop, 2007).
Dorsal epidermis intercalation

After forming two layers of epidermal precursors, the dorsal epidermis undergoes rearrangement to form a single row of epidermal cells across the dorsal surface of the
embryo, as Figure 4 explains. Prior to dorsal intercalation, epithelial stem cells
differentiate into epidermal cells, as mentioned previously. During dorsal
intercalation these cells become wedge-shaped and elongate their edges to contact
seam cells, as shown in Figure 4.1 b and c, with their tips pointed towards the midline.
Despite the details known about dorsal intercalation, mostly from observation, the
actual processes driving dorsal intercalation are still relatively unknown. However, it
is known that cytoskeletal elements (actin microfilaments and microtubules especially)
are involved in the generation of various cell protrusions, driving movement of the
epidermal cells (Chisholm & Hardin, 2005 and Zhang et. al, 2010).
Ventral enclosure

Ventral enclosure is the process of encasing the ventral embryo with a layer of
epidermal cells, as illustrated by Figure 4.2. Ventral enclosure begins with the
migration of ventral epidermal cells towards the midline, in a similar manner to the
migration of dorsal cells. This happens just after dorsal intercalation begins. After
this, the anterior cells move towards each other, progressing posteriorly. A ventral
pocket forms because the anterior cells fuse first, leaving a space without epidermal
cells to their posterior. The cells from opposite sides of the embryo will form
junctions once they are in contact at the ventral midline. Again, cytoskeletal elements
are required for movement of the ventral epithelial cells. With the ventral epidermis
enclosed, the entire embryo is now enclosed by a sheet of epidermis. It is also

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2
Figure 4: Dorsal intercalation and
ventral enclosure. In order to form a
uniform sheet of epidermal cells, the
dorsal and ventral surface epidermal
cells must expand, migrate and extend,
forming connections with one another. 1
shows dorsal intercalation while 2 shows
ventral enclosure. At 1A, the dorsal
epidermal cells, surrounded by
epidermal seam cells, elongate (1B) and
become wedge-shaped (1C) as they cover
the entire dorsal surface of the embryo
(1D). For ventral enclosure, the
epidermal cells originate from the
lateral surfaces of the embryo (2A) and
elongate anteriorly to posteriorly (2B),
forming a ventral pocket as the posterior
cells elongate towards the midline (2C).
Eventually, the ventral pocket closes and
encases the entire ventral surface of the
developing embryo, as shown in 2D
(Adapted from Chisholm & Hardin,
2005).

important to note that the head

epidermis must also enclose,
though its mechanisms have
not been exclusively
researched and thus little
information is known at
current (Chisholm & Hardin, 2005).
Stratification of the epidermis

Occurring, often concurrently, with the preceding events is the stratification of the
epidermis- the process of building the layers that compose the mature epidermis.
Stratification of the epidermis constitutes many steps, beginning with the development
of the basal layer of epidermal cells, as indicated by the orange layer of cells in Figure
5 (Koster & Roop, 2007). p63 is involved in the determination of this basal layer of
keratinocytes, which are highly proliferative. This change is also accompanied by a
switch in keratin expression and desmosomal components, again mainly under the
influence of p63. Because of the proliferative function of the basal layer giving rise to
all further keratinocytes of the epidermis, this function must be retained throughout
adult life as well. This is achieved by a high expression of p63 in the adult basal
epidermis, ensuring a constant supply of basal keratinocytes. It may also function to
inhibit inhibitors of the cell cycle, such as p21 (Koster, 2010). The next step in the
stratification of the epidermis is the formation of the intermediate cell layer (Figure 5
yellow layer), one of the first recognisable signs of epidermal stratification. The
intermediate cell layer develops between the periderm and basal layer as a result of
asymmetrical cell divisions within the basal keratinocytes. At present the only known

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difference between basal keratinocytes and intermediate layer keratinocytes is the

difference in mitotic activity (Koster & Roop, 2007). Again, p63 plays a role in
generating the intermediate cell layer from the basal keratinocytes, promoting the
differentiation towards intermediate keratinocytes (Koster, 2010). Notch signalling
may also be involved in generating and maintaining the intermediate cell layer. It is
important to note that in adults this transition does not occur. Instead, Notch
signalling transforms basal keratinocytes directly into spinous keratinocytes (Koster &
Roop, 2007). The next layer to form is the spinous layer (Figure 5 blue layer),
consisting of spinous keratinocytes that replace the intermediate cell layer. Spinous
keratinocytes are characterised by being in a post-mitotic state. Though divided, most
studies point to the concept that the intermediate cell layer cells directly give rise to
the spinous keratinocytes, without the need for apoptosis (Koster & Roop, 2007). p63
is again involved in the generation of this layer of cells and contribute to the postmitotic state of the differentiated spinous keratinocytes (Koster, 2010). The granular
layer of epidermis (Figure 5 purple layer) is the next to develop- generating from
maturing spinous keratinocytes. Granular keratinocytes have many granules of
keratin-like substances, preparing for their cornification at the epidermal surface
(Fuchs, 2008; and Koster & Roop, 2007). Driving this maturation is the presence of a
Ca2+ gradient across the epidermis, rising in concentration the more superficial the
cells get. The Ca2+ affects the cells in this way by acting upon various signalling
pathways, including that involving PKC (protein kinase C), which functions
exclusively during the spinous to granular cell layer transition. A specific role of a
Ca2+ sensing receptor is that it acts exclusively in the formation of the granular layer
of keratinocytes. The final step is the formation of the cornified (keratinised) external
barrier layer, as illustrated green in Figure 5. These cells are in fact dead keratinocytes
that will eventually be sloughed off. The maturation of granular keratinocytes to
cornified keratinocytes is one that involves the breakdown of organelles, the nucleus
and various proteins, effectively leaving the shell of a keratinocyte filled with keratin,
providing the strength and insolubility that the outer barrier requires. The cells also
form tight junctions with one another, fixing the cornified cells together and
preventing any unwanted access from the exterior (Koster & Roop, 2007). This
process is mediated by the Klf transcription factor, which promotes the formation of
the cornified layer. With the cornified layer now finished, the stratification of the
epidermis is complete. This process (without the formation of the intermediate cell
layer) is a continual process within the epidermis of adult skin, helping to perform
many of the various functions that we associated with the skin at the beginning of this
report (Koster & Roop, 2007).

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Figure 5: The stages of stratification of the epidermis. The epidermis begins as
a single layer of basal progenitors which then differentiate into the basal
keratinocytes (stratum gernivativum). These basal keratinocytes then procure
the intermediate layer of epidermal cells, a layer of cells only present in foetal
life. The periderm, a transient outer covering of epidermal cells, also forms on
top of the intermediate layer and will remain there until the formation of the
cornified barrier layer of dead keratinocytes later in foetal development. The
next layer to develop is the spinous layer of keratinocytes (stratum
mucosum/stratum spinosum), which cease to divide and replace the
intermediate layer of cells. The spinous keratinocytes then develop into
granular keratinocytes (stratum granulosum), which rapidly fill their cytoplasm
with keratin and remove organelles in preparation for their subsequent death,
contributing to the outer cornified layer of keratinocytes (stratum coreneum)
(Adapted from Koster & Roop, 2007).

The dermis: a mesodermally-derived connective

tissue
The dermis is a dense irregular connective tissue, composed
mainly of collagen fibres, fibroblasts, various molecules and
fluid, all intermingled with nerves, sweat glands, specialised
nerve endings and blood vessels. The cells within the
dermis include fibroblasts, adipocytes and macrophages.
The extra cellular matrix of the dermis occupies a vast
amount of space in which fluid, sugar-based molecules and
cells reside (Brouard & Barrandon, 2003; and Rutter, 2000).

The mechanical properties of the dermis, due to its collagen and elastin fibres, are
responsible for the mechanical properties of the skin. The dermis is also in
communication with the epidermal appendages (hair follicles, sebaceous glands, sweat
glands), which extend into the dermis. The dermis is highly vascularised and provides
nutrients to the overlying avascular epidermis. In addition, the dermis is wellinnervated, containing many different sensory receptors (free nerve endings,
Meissners and Pacinian corpuscles). , allowing us to receive sensation from the skin
(Brouard & Barrandon, 2003). The dermis also has layers like the epidermis,
consisting of the stratum papillare and stratum reticulare, as shown in Figure 6. The
loose connective tissue stratum papillare is more superficial and contains papillae,
projections that support the epidermis. It provides nutrients to the epidermis and also
houses a rich nerve supply. The stratum reticulare is dense connective tissue located
deeper than the stratum papillare. It contains deep blood vessels, skin appendages and
nerve receptors (Rutter, 2000). The development of the dermis is vastly different from
that of the epidermis, mainly due to the fact that the dermis is mesodermally-derived
whereas the epidermis is ectodermally-derived. During gastrulation, some epiblast

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cells of the bilaminar disc migrate through the primitive streak to form middle and
lower layers of cells underneath. The cells of the middle layer are those cells that give
rise to mesoderm tissues, such as the dermis (Loebel et. al, 2003). The dermis can be
divided into the dorsal and ventral dermis, the dorsal deriving from somites, clumps of
mesodermal tissue which progressively form either side of the midline after
gastrulation, and the ventral from the lateral plate mesoderm, a layer of mesodermal
cells lateral to the somites. The head and neck dermis, on the other hand, develops
from neural crest tissue (Ohtola etl al, 2008; and Widelitz, 2008). We will consider
the development of these different dermal regions separately.
Dorsal dermis

As somites develop, distinct regions form that give rise to different tissues. The
sclerotome cells (those cells on the ventral surface of the somite) will develop into
bone and cartilaginous tissue, such as the vertebrae. The remainder of the somite is
referred to as the dermomyotome, as it will give rise to muscle and mesenchymal cells
fated to become the dermis. With Wnt signalling, the cells of the dermomyotome
become fated to either develop into muscle or dermis. The dermomyotome can be
divided into dorsal, medial and lateral aspects. The medial and possibly lateral aspects
give rise to the dorsal dermis. Wnt signalling is involved in the determination of
dermal fate from the dermomyotome as well as during the specification of dermal cells
from the mesenchymal progenitors (Fuchs, 2007; Loebel et. al, 2003; and Widelitz,
2008).
Dermis

Stratum reticulare

Stratum papillare

Epidermis

A
D
C

Figure 6: The two subdivisions of the dermis- the stratum reticulare and stratum papillare. The stratum papillare
is the upper layer of the dermis that contains projections (papillae) that provide nutrients for the epidermis above

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as well as being the location for most of the skins nerve supply. The loose connective tissue stratum papillare is in
stark contrast to the layout of the dense connective tissue stratum reticulare. The stratum reticulare includes
deep appendages and blood vessels, but is most characterised by the densely packed nature of its fibroblasts,
elastin and collagen fibres, proteoglycans and other cells and molecules of the dermis. In this figure, many hair
follicles (A) can be seen both in the stratum reticulare and papillare, though those in the reticulare are more deep
and thus nearer to the bulb of the hair follicle. Many adipocytes (B) are also present within the stratum
reticulare. The underlying muscle (C) can also be seen. Though difficult to discern, many blood vessels (D) are
present meandering through both layers of the dermis, providing nutrients to the overlying epidermis as well as
the dermis itself.

Ventral dermis

The lateral plate mesoderm splits into two layers- the somatic layer and the splanchnic
layer. The splanchnic layer will develop into the mesoderm associated with viscera
whereas the somatic layer develops into the mesoderm tissues of the body wall and
limbs (including the ventral dermis). Wnt signalling is involved in differentiation of
the somatic layer into dermal progenitors. The dermal progenitor cells of the somatic
layer then migrate from their position towards the exterior surface of the embryo. The
three muscle layers surrounding the abdomen form as well as those in the limbs. The
mesenchymal cells form a sheet underneath the basal membrane of the epidermis and
lateral to the muscular layers forming beneath. These mesenchymal cells then
undergo differentiation to become dermal cells, such as adipocytes and fibroblasts
(Ohtola, et. al, 2008; and Widelitz, 2008).
Neural crest involvement
Though the ventral (body wall and limb) dermis and dorsal (back) dermis derive from
mesenchymal (mesodermal) precursors, the dermis of the head and neck derives from
the neural crest, a group of ectodermally-derived cells that form beside the neural tube
during neurulation. The cells of the neural crest must migrate from their dorsal
position towards the ventral surface of the head. Cells delaminate from the
epithelium, transferring from epithelial cells to mesenchymal cells. They then migrate
due to various factors, such as fibronectin and neural cell adhesion molecule, through
extra-cellular matrix to their target tissue. The head neural crest cells move towards
areas that will become the pharynx and face. Once they have migrated, some cells
will begin to differentiate into dermal cells. Other cells will migrate into the epidermis
and differentiate into melanocytes, the pigment-producing cells of the skin. All
melanocytes of the body are derived in this manner, not just those that give rise to
head and neck melanocytes (Widelitz, 2008).
Epithelio-mesenchyme interactions
Molecular controls of hair follicle formation

Coinciding with the introduction of mesenchymal cells from the lateral plate
mesoderm is the formation of hair placodes (see Figure 9), induced by these
mesenchymal cells. BMP signals from the msesenchymal cells promote the formation
of the placodes. These small epidermal invaginations from the epidermis into the

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dermis are also instructed to form by Wnt signalling in the epidermis (Brouard &
Barrandon, 2003; and Fuchs, 2007). The placode then begins to express Sonic
hedgehog (Shh), prompting the formation of a structure known as the dermal papilla,
which instructs the hair placode to grow downwards into the dermis, forming a hair
follicle. Figures 7, 8 and 10 illustrate the histology of hair follicles and their
associated structures in transverse mouse sections, both on large-scale and magnified
images. The maturation of the hair follicle takes place via various epitheliomesenchymal interactions. Both Wnt singnalling and Lef1 proteins are heavily
involved in the morphogenesis of the hair follicle from its placode to matured form.
An important regulator during hair follicle maturation is Shh, which has been shown
to progress the hair follicle past the germ cell stage (Blanpain & Fuchs, 2006; Fuchs,
2007; and Widelitz, 2008). Complex inhibitory mechanisms also regulate the
development and maturation of hair follicles, one such example being the Wnt
inhibitory pathway. Also, the dermis influences many aspects of the development of
the hair follicle, especially hair follicle size and density. The presence of placodepromoting and placode-inhibiting factors within the epidermis also adds to the
complexity of molecular regulation of the hair follicle developmental pathway (Fuchs,
2007).
B
D

Figure 7: Transverse section of skin hair follicles. This figure shows many different hair follicles (A) in the
stratum reticulare of the dermis. Many different parts of the hair follicle can also be visualised, such as the hair
shaft (B) and the hair bulb (C). The hair bulb contains the progenitors of the rest of the hair follicle, giving rise to
the four main types of cells in the mature hair follicle- the hair shaft cells, the inner root sheath cells, the outer
root sheath cells and the companion cells which lie in between the outer root and inner root sheaths. The hair
bulb is in contact with the dermal papilla, which is of mesodermal origin and acts as a signal to continue the
proliferation of the progenitor cells within the hair bulb. Additionally, the hair follicles are surrounded by many
adipocytes (D).

Structure and development of the hair follicle

Having explored some molecular controls of hair follicle formation, we will now
consider how the various structures of the hair follicle form. As the hair follicle

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begins to encroach into the dermis, those cells that remain in contact with the dermal
papillae continue to proliferate rapidly while those trailing behind the dermal papillae
undergo differentiation. The cells that are still in communication with the basal
lamina form the outer root sheath while those cells not in communication with the
basal lamina form the inner root sheath, which will provide a canal for the developing
hair shaft (Blanpain & Fuchs, 2006; and Fuchs, 2007). Thereafter, a group of cells
internal to the inner root sheath develop and begin to form the hair shaft under the
action of Shh, as Figure 9 E18 illustrates. At this time, sebaceous gland precursors
also begin to develop on the side of a developing hair follicle. Notch signalling then
plays a part in differentiating hair shaft cells and the inner root sheath cells.
Maturation of the hair follicle ensues and a new layer of cells, called the companion
layer, forms between the inner and outer root sheaths. The inner root sheath and hair
shaft cells then multiply to form three-cell thick rings with the hair shaft cells more
interior than the inner root sheath. This structure gives rise to the hair shaft proper.
The hair follicle now consists of seven layers arranged into ringed structures from
internal hair shaft to external outer root sheath (P4 of Figure 9) (Fuchs, 2007). The
sebaceous gland cells also continue to develop from the side of the hair follicle. The
sebaceous gland cells, sebocytes, continue to mature, though will not be fully matured
until shortly after birth. The function of these cells is to secrete lipids and an oily
substance called sebum that coats the external surface of the skin in mammals. This
occurs when terminally differentiated sebocytes die, releasing their cell contents.
Thus, a continually regenerating population of sebocytes must be maintained within
each sebaceous gland (Brouard & Barrandon, 2003; and Fuchs, 2007). Hair follicles
are also surrounded by muscular cells derived from mesoderm which form a muscular
bundle, called the arrector pilli, which attaches to the epidermal surface and makes the
hair follicle stand on end when it contracts (Blanpain & Fuchs, 2006). Though not
discussed in any detail here, the structure and development of feathers is similar to
hair follicles, though with some notable exceptions (Widelitz, 2008).
Adult hair cycle

Having produced new hair follicles (either in utero or just after birth), they must now
be renewed throughout life- a constant process known as the hair cycle. The hair
cycle can be broken into three main phases: anagen, catagen and telogen. Anagen is
similar to the embryonic development of the hair follicle described earlier- it consists
of a period of growth and differentiation of the hair follicle. During this time, the
matrix cells of the hair bulb are proliferating. Once they exhaust their proliferative
nature or lack a required signal, the period of anagen stops. Following anagen is
catagen, a phase of programmed cell death within the hair follicle. The transition
between anagen and catagen is proposed to be regulated by keratin-17. In catagen, the
hair follicles size reduces vertically, taking with it the dermal papilla. The catagenic
phase stops when the permanent upper region of the hair follicle is reached (roughly
the top third of the hair shaft). Telogen, a phase of resting, then ensues. Anagen will

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then resume growth of the hair follicle, and the cycle will begin again (Blanpain &
Fuchs, 2006; and Fuchs, 2007).
Epidermal and dermal interaction during development

Our exploration of the hair follicle provided a good example of a common epitheliomesenchymal interaction during development. However, it is not the only one. Other
interactions include epidermal specification, the development of other appendages,
thick verses thin skin specification, epithelial polarisation, proliferation and
stratification of skin tissue and the formation of species-specific structures such as
hair, feathers and scales (Sengel, 1990). During epidermal specification, the
underlying dermis provides the inductive signals required to create a region-specific
epidermal skin layer. For example, an underlying dermal layer from the scalp will
induce epidermal scalp skin. This has been proven in an experiment whereby skin
from different regions was combined with different underlying dermal tissues, always
procuring an overlying epidermis that follows the established fate of the underlying
dermis. In determining whether an overlying epidermis will be thick skin (thick
cornified layer) or thin skin (thin cornified layer), the underlying mesenchyme is again
involved, prompting the expansion of the cornified layer in areas such as the soles of
the feet and palms of the hands in humans. The induction of sweat glands, hair
follicles, scales, feathers, sebaceaous glands and arrector pilli muscles also have their
origins with dermal interaction (Fuchs, 2007; and Ohtola et. al, 2008).

D
B

Figure 8: A close-up of a hair follicle and associated dermis. The base of the hair follicle (A), the region full of
hair follicle progenitors, can be easily discerned. The dermal papilla (B), the mesodermally-derived tissue that
keeps the hair cell progenitors proliferating, is also visible. Blood vessels (C) with erythrocytes supplying the hair
follicle with its required nutrients and their endothelial cell lining (E) are both illustrated in the figure. Some
mitotic cells, such as D, are also present since the skin is a highly proliferative tissue. The difference between the
stratum papillare (F), a loose connective tissue, and the stratum reticulare (G), a dense connective tissue, is also
discernible. It would also be expected that sebaceous gland cells (sebocytes) and hair follicle-associated arrector
pilli muscle cells would be present towards the apex of the hair follicle.

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Figure 9: The foetal development

of the hair follicle contributes to
the structure of the mature hair
follicle. Guided by dermal signals,
hair folliculogenesis begins from
the basal lamina of the epidermis
at locations known as placodes
where the epidermal cells
invaginate and begin to migrate
downwards into the dermal space.
Dermal signalling then continues to
specify growth and extension of the
primitive hair follicle and produces
three distinct lineages from the
hair bulb progenitor cells- the
inner root sheath cells, the outer
root sheath cells and the hair
matrix cells. The dermal papilla
also develops, ensuring the
proliferative growth of the
epidermal hair bulb progenitors.
The hair follicle continues to
mature and eventually gathers
another layer of cells, the
companion layer between the outer
and inner hair sheaths as well as
the sebaceous gland cells
(sebocytes) from sebaceous gland
progenitors and the arrector pilli
muscle cells that stand the hair
follicle on end. The maturation of
the hair follicle is accompanied by
the maturation of matrix cells into
hair cell progenitors, which
themselves give rise to the hair
shaft proper. Thus a complete socalled pilo-erector unit is formed at the end of foetal development or shortly after birth, providing thin skin areas
with hair follicles and their associated structures (Taken from Blanpain & Fuchs, 2006).

Abnormalities of the skin

Ectodermal dysplasias are a group of over 150 disorders that are characterised by
developmental errors in the ectoderm, especially the epidermis and associated
appendages. Considering the importance of p63 in epidermal development, mutations
in the TP63 gene that encodes this critical protein underpin many ectodermal
dysplasias, including ectrodactyly-ectodermal dysplasia-cleft (EEC) syndrome and
Hay-Wells syndrome. Though both caused by p63 mutations, they have very different
presentations. EEC is characterised by ectrodactyly, a malformation of the central
digits of the hand or foot resulting in a claw-like appearance; overall ectodermal
dysplasia, facial clefts, such as cleft lip and/or cleft palate; as well as limb
abnormalities. Hay-Wells syndrome is characterised by sparse hair and eyelashes,
malformed nails, missing teeth, cleft palate and skin erosions. Both syndromes are
autosomal dominant, both located to chromosome 3q. Both are thankfully very rare
disorders, though often run in families because of their autosomal dominant nature.

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The vast differences between these two disorders can be explained by the differences
in their mutations. EEC is caused by mutations in the TP63 gene corresponding to the
N-terminus or C-terminus whereas Hay-Wells mutations correspond to the DNA
binding domain of p63. There are also various other p63 disorders, all of which are
autosomal dominant and result in a defective or absent p63 protein. Much more
research is needed to understand the molecular pathways of these disorders, possibly
unearthing possible treatments and therapies or preventative measures for these
physically-deforming disorders (Koster, 2010).
Development of the Skin: major themes
Having explored the structure, development and abnormalities of the skin and its
various appendages, layers and structures, let us re-cap some of the major themes that
underpin the development of the skin. The themes that we have explored are: the
molecular control of signalling during development, epithelial-mesenchymal
(epidermal-dermal) interactions, the influence of morphogenic gradients, cell mobility
and cell communication in the development of the skin, the genetic mechanisms
behind these actions and the abnormalities that can arise as a result of incorrect
development of the skin. This report has explored these various themes in relation to
the two main gross layers of the skin- the epidermis and dermis. The structure of the
skin, its various layers and appendages were related to the main functions of the skin.
Development of the skin, divided into its ectodermally-derived epidermis and
mesodermally-derived dermis, was also explored in depth. This gives us a grand
appreciation for the role that the skin has in maintaining life and the complex array of
developmental processes needed to construct, regenerate and recycle the multitude of
components that comprise the integumental system.
References
Blanpain, C & Fuchs, E 2006, Epidermal stem cells of the skin, Annual Review of
Cell Developmental Biology, vol. 22, pp. 339-373
Brouard, M & Barrandon, Y 2003, Controlling skin morphogenesis: skin and
despair, Current Opinion in Biotechnology, vol. 14, pp. 520-525
Chisholm, A.D. & Hardin, J. 2005, Epidermal morphogenesis, WormBook, vol. 1,
pp. 1-22
Chuong, CM, Nickoloff, BJ, Elias, PM, Goldsmith, LA, Macher, E, Maderson, PA,
Sundberg, JP, Tagami, H, Plonka, PM, Thestrup-Pedersen, K, Bernard,
BA, Schrder, JM, Dotto, C, Chang, CH, Williams, ML, Feingold, KR,
King, LE, Kligman, AM, Rees, JL & Christopers, E 2002, What is the
true function skin?, Experimental Dermatology, vol. 11, pp. 159-187
Fuchs, E 2007, Scratching the surface of skin development, Nature, vol. 455, no.
7130, pp. 834-842
Koster, MI & Roop, DR 2007, Mechanisms regulating epithelial stratification,
Annual Review of Cell and Developmental Biology, vol. 23, pp. 93-113

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Koster, MI 2010, p63 in skin development and ectodermal dysplasias, Journal of

Investigative Dermatology, vol. 130, pp. 2352-2358
Loebel, DA Watson, CM, Young, AD & Tam, PP 2003, Lineage choice and
differentiation in mouse embryos and embryonic stem cells, Developmental
Biology, vol. 264, pp. 1-14
Mancini, AJ 2004, Skin, Pediatrics, vol. 113, no. 4, pp. 1114-1119
Ohtola, J, Myers, J, Akhtar-Zaidi, B, Zuzindlak, D, Sandesara, P, Yeh, K, Mackem, S
& Atit, R 2008, -catenin has has sequential roles in the survival and
specification of ventral dermis, Development, vol. 135, no. 13, pp. 23212329
Rutter, N 2000, Dermis, Seminars in Neonatology, vol. 5, no. 4, pp. 297-302
Sengel, P 1990, Pattern formation during skin development, International Journal of
Developmental Biology, vol. 34, pp. 33-50
Widelitz, RB 2008, Wnt signalling in skin organogenesis, Landes Bioscience, vol. 4,
no. 2, pp. 123-133
Zhang, H, Gally, C & Labouesse, M 2010, Tissue morphogenesis: how multiple cells
co-operate to generate a tissue, Current Opinion in Cell Biology, vol. 22 pp.
575-582