an exploration of the development and morphogenesis of skin

P a g e | 1 Brent Connolly

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; Langerhan’s

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).


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.

Figure 2: Epidermal and dermal skin layers: The layers of the epidermis, a stratified squamous epithelium, - A-

Stratum 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).

A

B

D

G

C

E

B

F

A

B

C

E

F

Dermis

Epidermis

D

H


Figure 3:

From the beginning: zygote to gastrulation

Figure 3: Gastrulation leads to three germ layers that 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.


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, Merkel’s 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 (FGF’s), resulting in ectoderm expressing Bone

Morphogenic Proteins (BMP’s) instead. The expression of BMP’s in ectoderm results

in epidermis, while the expression of FGF’s 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


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 re-

arrangement 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


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

1 2


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 post-

mitotic 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).


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 well-

innervated, containing many different sensory receptors (free nerve endings,

Meissner’s 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


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).

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

Epidermis Stratum papillare Stratum reticulare

Dermis

A

B

C

D


as well as being the location for most of the skin’s 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


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 epithelio-

mesenchymal 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 placode-

promoting and placode-inhibiting factors within the epidermis also adds to the

complexity of molecular regulation of the hair follicle developmental pathway (Fuchs,

2007).

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

A

B

C

D


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 follicle’s 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


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 epithelio-

mesenchymal 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).

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.

C

B A

D E

F

G


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 so-

called 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.


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.

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an exploration of the development and morphogenesis of skin

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