Lecture - Integumentary Development

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Introduction

Adult skin histology showing epidermis, dermis and hypodermis as well as specializations, such as hair follicles and sweat glands

The skin provides a barrier between ourselves and our environment (temperature, water, UV), and contains specializations in different regions including hair, nails, teeth, glands and sensory receptors. In other species there are also specializations of beaks, scales and feathers.

The two major tissue organizations of epithelial (ectoderm, epidermis) and mesenchyme (mesoderm connective tissue, dermis and hypodermis) are shown within skin. In addition, we have also have extensive populating by melanocytes (neural crest) and sensory nerve endings.

Possibly the first epithelial tissue specialization from which arose other epithelial specializations now located inside the body. The external skin associated structures have many different roles and functions. This system is also an excellent model for distribution or "pattern" and adult stem cells.

A PDF of the lecture slides can be found here: File:ANAT2341 Lecture 4 - Beverdam - Integumentary System.pdf


Podcast icon.jpg Lectopia Lecture Audio

Lecture 18 - Integumentary Development

Lecture Date: 2013-10-08 Lecture Time: 16:00 Venue: Biomedical Theatre E Speaker: Annemiek Beverdam

Textbooks

Embryology

Logo.png Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.
Integumentary Links: Introduction | Lecture | Hair | Tooth | Nail | Gland | Mammary Gland | Eyelid | Outer Ear | Touch | Histology | Abnormalities | Category:Integumentary
Historic Embryology
1910 Manual of Human Embryology | 1923 Head Subcutaneous Plexus | 1921 Text-Book of Embryology | Historic Disclaimer
| 2010 Lecture


The Developing Human: Clinically Oriented Embryology

The Developing Human, 9th edn.jpg Citation: The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011. (links available to UNSW students)

Larsen's Human Embryology

Larsen's human embryology 4th edn.jpg Citation: Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009. (links available to UNSW students)
Links: Embryology Textbooks

Objectives

  • Understand the embryonic origin and differentiation of the epidermis and dermis.
  • Understand the formation of hair and nails.
  • Understand the formation of sweat glands, mammary glands.
  • Understand the formation of teeth.
  • Brief understanding of associated abnormalities.
Skin structure cartoon.jpg

Skin structure cartoon

Skin Origins

Embryo epidermis (Stage 13)
Human Embryo (Week 8, Stage 22) Integument

Skin is our largest organ, providing a protective layer between us and our environment

  • Ectoderm forms the surface epidermis and the associated glands.
  • Mesoderm forms the underlying connective tissue of dermis and hypodermis.
  • Neural crest cells also migrate into the forming epidermis and the skin is also populated by specialized sensory endings.
  • epithelia/mesenchyme (ectoderm/mesoderm) interaction an inductive manner (see lecture on kidney)
  • 2 main types of histological skin - thin (most of body) thick (soles of feet and hands) based on ectoderm, not the thickest skin including dermis (top of back)

Regional Specializations

  • skin has different structures associated with different regions of the body
  • nails, hail, glands, teeth, eyelashes, eyebrow

Development Overview

Human embryo cornea and eyelid (Stage 22, week 8)

4 weeks

  • simple ectoderm epithelium over mesenchyme.

1-3 months

  • ectoderm - germinative (basal) cell repeated division of generates stratified epithelium.
  • mesoderm - somite dermatome spreads out under the epithelium, differentiates into connective tissue and blood vessels.

4 months

  • basal cell - proliferation generates folds in basement membrane.
  • neural crest cells - (melanocytes) migrate into epithelium. These are the pigment cell of the skin.
  • embryonic connective tissue- differentiates into dermis, a loose connective tissue (ct) layer over a dense ct layer. Beneath the dense ct layer is another loose ct layer that will form the subcutaneous layer.
  • Ectoderm contributes to nails, hair follicles and glands.
  • Nails form as thickening of ectoderm epidermis at the tips of fingers and toes. These form germinative cells of nail field.
  • Cords of these cells extend into mesoderm forming epithelial columns. These form hair follocles, sebaceous and sweat glands.

5 months

  • Hair growth initiated at base of cord, lateral outgrowths form associated sebaceous glands.
  • Other cords elongate and coil to form sweat glands.
  • Cords in mammary region branch as they elongate to form mammary glands. These glands will complete development in females at puberty. Functional maturity only occurs in late pregnancy.

Fetal integumentary histology 01.jpg

Fetal human integumentary histology[1] (Weeks in figure are from LMP)

Epidermis

Electron Micrographs of the Developing Human Epidermis[2]

Human embryo skin 8-9 week EGA.jpg

8-9 week EGA

Human embryo skin 9-11 week EGA.jpg

9-11 week EGA

Human embryo skin 24 week EGA.jpg

24 week EGA

Adult epidermis histology
  • week 4-5 - early skin is a single ectodermal layer, stratum germinativum basal layer. (periderm cells are replaced continuously until 21 weeks)
  • week 11 - forms intermediate layer.
  • week 19-21 - periderm then lost replaced by stratum corneum, keratinization and disqualification.
  • week 10 epidermial ridges are formed by proliferation.

Human embryo skin 8-9 week EGA desmosomes.jpg

Human embryo skin desmosomes (8-9 week GA)

Neural crest cells

Melanoblast migration
  • Neural crest cells migrate into skin (late embryonic) form melanoblasts
  • day 40-50 differentiate into then melanocytes - form pigment granules
  • different content of melanin (Greek, melas = "black") accounts for differet skin colour

Melanoblast Migration - Quicktime | Flash

Dermis

Dermal pattern fingerprint
  • lateral plate mesodermal in origin
  • forms connective tissue
  • afferent nerves influence dermal ridge formation

Blood Vessels

  • lateral plate mesodermal in origin
  • week 5 - blood vessels form in mesenchyme
  • form capillary beds, extensive remodelling with development

Skin Dermatomes

Dermatomes
  • pattern of skin innervation
  • area supplied by single spinal nerve
  • motor and sensory DRG
  • cutaneous nerve area

Keratin

  • large family of intermediate filament protein, 17+ isoforms
  • skin disease associated with mutations in keratin genes

Cornification

A form of cell death that occurs in the adult skin epithelium and occurs in the upper layers (granular layer and stratum corneum). Cornified envelope is the formation or ‘keratinization’ is specific of the skin to create a barrier function, exclusive to the upper layers (granular layer and stratum corneum).

  • Elimination of cytosolic organelles
  • Modifications of plasma membrane
  • Accumulation of lipids in keratohyalin granules in stratum granulosum
  • Extrusion of lipids in the extracellular space
  • Desquamation (loss of corneocytes) by protease activation


Links: Cell Biology - Cell Death

Development of Glands

Newborn - vernix caseosa
  • 2 main types - sebaceous and sweat
  • both ectodermal in origin
  • form as ingrowth of ectoderm into the mesoderm

Sebaceous

  • associated with hair development
    • except plans penis and labia minora
  • these glands secrete vernix

Sweat Glands

  • mostly eccrine some apocrine
  • apocrine in axilla, pubic and nipple regions
    • see also mammary gland development

Vernix Caseosa

  • (Latin, vernix caseosa = varnish , cheese-like) (Dunglison Dictionary of Medical Sciences, 1846)
  • covers fetal skin - secretion from sebaceous glands
    • consists of water (81%), lipid (9%), and proteins (10%)
  • possibly unique to human development
  • protects skin from extraembryonic fluids amnion, urine
  • slippery and helps with parturition
  • transition from intrauterine to neonatal extra-uterine life
  • suggested to have many different roles

Mammary Glands

Fetal mammary gland (16 cm CRL)

Mammary anatomy
  • week 6 epidermis downgrowth into dermis, modified sweat glands
    • epithelia/mesenchyme inductive interaction, mesenchyme forms connective tissue and fat
  • mammary ridges - mammary bud formation, pair of ventral regions axilla to inguinal
    • pectoral regions generate breasts
  • buds branch to form lactiferous ducts, only main duct formed at birth
  • mammary pit - forms fetal period
  • areola - depressed region at gland, proliferation of connective tissue postnatally
  • prior to puberty male and female glands the same

Puberty

  • sex hormone estrogen stimulate growth, full development approx 20 years
  • growth also influenced by other hormones - progereterone, prolactin, corticoids, growth hormone
  • mainly fat and connective tissue deposition

Pregnancy

  • raised estrogens and progesterone stimulate gland development
  • hemispherical shape due to fat deposition
  • lactation supports development

Breast cancer

  • In 1994, two breast cancer susceptibility genes were identified: BRCA1 on chromosome 17 BRCA2 on chromosome 13
  • When an individual carries a mutation in either BRCA1 or BRCA2, they are at an increased risk of being diagnosed with breast or ovarian cancer at some point in their lives. Normal function of these genes was to participate in repairing radiation-induced breaks in double-stranded DNA. It is though that mutations in BRCA1 or BRCA2 might disable this mechanism, leading to more errors in DNA replication and ultimately to cancerous growth.

Breast Cancer Detection - reduce mortality is through early detection (general screening of the population for BRCA1 and BRCA2 is not yet recommended). New strategies to find anti-cancer drugs are constantly being developed. The latest, called 'synthetic lethal screening' looks for new drug targets in organisms such as yeast and fruit flies. In the same way that studies in yeast recently helped to identify the functions of BRCA1 and BRCA2, it is thought that drugs that work in more primative organisms will also be applicable to humans.

Links: Mammary Gland Development

Hair Development

Hair development stages

Hair formation, or follicle development, is an example of two distinct developmental processes: epithelio-mesenchymal interactions and pattern formation. The differentiated hair follicle will eventually contain 20 or more different cell types. Melanocytes, which provide the hair colour, have a neural crest origin, and with ageing their numbers decline leading to whitening (grey) of the hair process.

Hair follicle development in humans begins as an epithelial-mesenchymal interaction at week 9 - 12. This initial lanugo hair is replaced in the late fetal or early neonate by vellus and terminal hairs. A second round of development occurs during puberty under the influence of steroidal hormones (More? Puberty).

  • Before birth we have embryonic hair that has an imporant role in binding the skins waxy protective coating against our watery environment.
  • After birth we have early postnatal hair that is gradually replaced by the mature form.
  • At puberty we have a second round of hair formation under endocrine regulation by sex hormones.
  • The hair follicle is also a site for stem cells, allowing replacement of the follicle.

Hair Follicle

  • follicle forms in stratum germinativum of epidermis
  • hair bud then hair bulb forms hair
  • mesenchyme forms hair papilla
  • germinal matrix cells become keratinized to form hair shaft
  • week 12 - lanugo hair (Latin, lana = wool) - first hair formed replaced postnatally, role in binding vernix to skin
  • arrector pili muscle - develop in mesenchyme and form the muscles that move hair.
  • hair colour - melanocytes (neural crest) produce melanin which influences hair colour.
  • Puberty - coarse hair in pubis and axilla in both male and female (in males also on face and other body regions chest, etc)

Fetal Hair

  • Month 5 - hair appears on the head and beginning of vernix caseosa deposition.
  • Month 6 - body is covered by fine hairs (lanugo) and the deposit of vernix caseosa is considerable. Skin papilla are developed and the free border of the nail projects from the corium of the dermis.
  • Month 8 - skin now completely coated with vernix caseosa, and the lanugo begins to disappear. Skin is also pink in colour and subcutaneous fat being deposited (hypodermis layer).
  • Month 9 - lanugo has largely disappeared from the trunk.

Lanugo Hair

  • From about the third month lanugo hair (Latin, lana = wool) hiar is initially formed and it has a role in binding vernix to skin.
  • Hair grows over the entire body at the same rate, so the hairs are the same length, and is shed abut 4 weeks before birth. Premature infants can still be covered with these hairs.

Neonatal Hair

Neonate hair

Newborn infants have two types of hair:

  • Vellus Hairs - short hairs, only a centimetre or two long, and contain little or no pigment, follicles that produce them do not have sebaceous glands and never produce any other kind of hairs
  • Terminal Hairs - long hairs that grow on the head and in many people on the body, arms and legs, produced by follicles with sebaceous glands, the hairs in these follicles gradually become thinner and shorter until they look like vellus hairs

Hair Follicle Phases

There are several phases of hair follicle growth.

  • Anagen Phase - active phase
  • Catagen Phase - apoptosis-driven involution, end of active growing phase of the life cycle of the hair, between growing phase (anagen) and resting stage (telogen).
  • Telogen Phase - hair follicle resting phase of hair growth cycle.

Puberty Hair Development

The appearance of pubic hair occurs along with ther secondary sexual characteristics (also Tanner staged) and is under endocrine control.

  • Estrogens- (1 beta-estradiol, E2) involved in skin physiology and are potent hair growth modulators.
  • Testosterone- Face, trunk and extremities increases hair follicle anagen phase (active) and increases also hair growth rate, thickness, medullation and pigmentation. Effects due to high hormone levels and target organ conversion to 5 alpha-dihydrotestosterone. Pubic hair develops even in absence of 5 alpha-reductase effect.
  Tanner Stage   Pubic Hair Development
  1   None
  2   Few darker hairs along labia or at base of penis
  3   Curly pigmented hairs across pubes
  4   Small adult configuration
  5   Adult configuration with spread onto inner thighs
  6   Adult configuration with spread to linea alba

Table based upon the Tanner stages of secondary sexual development.[3]

Links: Hair Development

Nail Development

Nail structures
Neonatal nail
  • Forelimb before hindlimb - week 10 fingernails, week 14 toe nails
  • nail field - appears at tip and migrates to dorsal surface
  • thickened epidermis - surrounding cells form nail fold
  • keratinization of proximal nail fold forms nail plate

Nails reach Digit Tip

  • week 32 fingernails
  • week 36 toenails
    • nail growth indicator of prematurity

Nail Terms

  • nail plate - visible part of the nail
  • nail bed - skin beneath the nail plate
  • cuticle - tissue that overlaps the plate and rims the base of the nail
  • nail folds - skin folds that frame and support the nail on three sides
  • lunula - half-moon at the base of the nail
  • matrix - hidden part of the nail unit under the cuticle


Links: Nail Development | Embryo Images - Human (day 64) primary nail fields

Teeth

Fetal Head (12 weeks) lateral
Section of developing tooth from a 3 months human fetus
Deciduous teeth
Permanent teeth
  • integumentary system specialization by epitheilal/mesenchymal interactions in development and develops with a major contribution from the neural crest.
    • ectoderm of the first pharyngeal arch and neural crest, ectomesenchymal cells.
  • week 6 - odontogenesis begins, tooth bud
  • 4 morphological stages describing the early tooth development: bud, cap, bell, and terminal differentiation


Tooth Stages

Tooth stage lamina.jpg

lamina

Tooth placode stage.jpg

placode stage

Tooth bud stage.jpg

bud stage

Tooth cap stage.jpg

cap stage

Tooth bell stage.jpg

bell stage

  • 2 sets of teeth: 20 deciduous teeth, 32 permanent teeth
  • differential rates of growth, shed at different times over 20 year period
  • ectoderm, mesoderm and neural crest mesenchyme contribute
  • inductive influence of neural crest with overlying ectoderm
  • tooth growth occurs in ossifying jaws

odontoblasts

  • neural crest-derived mesenchymal cells which differentiate under the influence of the enamel epithelium. Cells secrete predentin, calcifies to form dentin.

ameloblasts

  • inner enamel epithelium forms pre-ameloblasts differentiate and produce enamel

periodontal ligament

  • tooth is not anchored directly onto its bony socket (alveolar bone) but held in place by the periodontal ligament (PDL), a specialized connective tissue structure that surrounds the tooth root coating of cementum.
  • ligament also act as; a shock absorber, transmitter of chewing forces (from tooth to bone), sensory information (heat, cold, pressure and pain).
    • collagen fiber bundles within the ligament are called "Sharpey's fibres".

Teeth Postnatal

Deciduous teeth

  • 6 - 24 months - erupt from gums by pushing toward surface
  • 2 years - all deciduous teeth present

Permanent teeth

  • 6 years until early adult
  • tooth bud lie in gums beneath deciduous teeth
  • osteoclasts resorb deciduous teeth roots
  • growth affects face shape
Links: Tooth Development

Abnormalities

The list below represents only a selection of associated abnormalities.

Skin

  • Ehlers-Danlos Syndrome - (EDS I and EDS II) loose-jointedness and fragile, bruisable skin that heals with peculiar scars. The syndrome is caused by mutation in the collagen gene. Infants are born prematurely due to premature rupture of fetal membranes.
  • Epidermolysis Bullosa Simplex - autosomal dominant disease of keratin, generating skin fagility and non-scarring blisters of the skin caused by little or no trauma. Four clinical subtypes: 1. EBS - Weber-Cockayne - mild blistering of the hands and feet 2. EBS - Koebner, 3. EBS - mottled pigmentation, 4. EBS - Dowling-Meara - generalized blistering which can be fatal.
  • Autosomal Recessive Congenital Ichthyosis - an excessive keratinization disorder.
  • Cutis Aplasia - congenital absence of the skin, particularly on the scalp, larger defects may extend to the dura or meninges. Generally isolated lesions, but can also be associated with a variety of other genetic disorders. Heals as a flat scar or keloid lump.
  • Incontinentia Pigmenti - X-linked dominant disorder with most but not all cases affecting females. The skin changes follow characteristic four stages. In the neonatal period the first stage is noted with blisters often preceded or accompanied by erythema. These involve any part of the body but usually not the face. They do not cross the midline. These lesions are best seen in the second photograph in the groin and suprapubic region. The lesions follow a linear distribution in the limbs and circumferentially around the trunk. Crops of lesions may occur over a period of weeks to few months. During that stage, peripheral eosinophilia may be noted. The second stage follows and is characterised by hyperkeratosis or verrucous changes. At times the 2 stages occur simultaneously as noted in the first and third photograph. The third stage is that of hyperpigmentation typically appearing as streaks or whorls. It may be present throughout childhood. The fourth stage seen in teenage or adults is that of pale or atrophic streaks.
  • Haemangiomas - relatively common (10% of infants), more common more common in preterm infants and girls. Initially present neonatally as a small "spot" or blanched vascular area which grows over the next 6 months before gradually involuting, usually over the next few years.

Breast

  • occurs in 1% of female population
  • polymastia - extra breast
  • polytheli - extra nipple, supernumerary nipple (relatively common in males)

Hair

  • androgenetic alopecia - male- and female-pattern hair loss.
  • telogen effluvium - alteration of the normal hair cycle, due to many different stress stimuli (severe stress, chemotherapy, childbirth, major surgery, severe chronic illness, rarely occurance in vaccination)
  • alopecia areata - autoimmune disease, form antibodies against some hair follicles, distinct circular pattern of hair loss.

Nail

  • Congenital hyponychia or anonychia - (hyponychium is the thickened epidermis beneath the free distal end of the digit) fingernails and toenails are absent without significant bone anomalies.
    • Total anonychia congenita - all absent, is a rare condition and may have an autosomal dominant inheritance patternis a rare condition, potentially autosomal dominant inheritance.
  • Nail-patella syndrome - small, poorly developed nails and kneecaps, autosomal dominant inheritance.
  • Ectodermal dysplasias - group of syndromes all deriving from abnormalities of the ectodermal structures.
  • Brachydactylies

Teeth

  • adontia - total lack of tooth development.
  • amelogenesis imperfecta - abnormal tooth enamel formation (AMELX, ENAM, KLK4, MMP20).
  • dentinogenesis imperfecta - discoloured teeth with an opalescent sheen, dentin does not support enamel (dentin sialophosphoprotein mutation)
  • dens evaginatus - dental anomaly mainly affecting premolars in people of Mongolian origin.
  • hypodontia - lack of development of one or more teeth.
  • hypohidrotic ectodermal dysplasia - maldevelopment of one or more ectodermal-derived tissues.
  • microdontia - small teeth.

References

  1. Neeltje A Coolen, Kelly C W M Schouten, Esther Middelkoop, Magda M W Ulrich Comparison between human fetal and adult skin. Arch. Dermatol. Res.: 2010, 302(1);47-55 PMID:19701759 | PMC2799629 | Arch Dermatol Res
  2. B A Dale, K A Holbrook, J R Kimball, M Hoff, T T Sun Expression of epidermal keratins and filaggrin during human fetal skin development. J. Cell Biol.: 1985, 101(4);1257-69 PMID:2413039 | PMC2113922
  3. Tanner JM. Growth at Adolescence. 2nd ed. Oxford: Blackwell Scientific, 1962.
  • Before We Are Born (5th ed.) Moore and Persaud Chapter 21: P481-496
  • Essentials of Human Embryology Larson Chapter 14: P303-315
  • Color Atlas of Clinical Embryology Moore Persaud and Shiota Chapter 15: p231-236

Online Textbooks

Terms

dermal papilla - the extensions of the dermis into the epidermis.

dermatoglyphic patterns - (Greek, derma = "skin", glyph = "carving") fingers, palms, toes, and soles skin patterns.

epidermal growth factor receptor - expressed on cells in the epidermis basal layer, signaling stimulates both epidermal growth and wound healing and also mediates an inhibition of differentiation.

rete ridge - the extensions of the epidermis into the dermis. These epidermal surface thickenings extend downward between underlying connective tissue dermal papillae. This is also the site of initial eccrine gland differentiation.

External Links

External Links Notice - The dynamic nature of the internet may mean that some of these listed links may no longer function. If the link no longer works search the web with the link text or name.

Olivier Duverger, Maria I Morasso Role of homeobox genes in the patterning, specification, and differentiation of ectodermal appendages in mammals. J. Cell. Physiol.: 2008, 216(2);337-46 PMID:18459147 | Figure 1 Key steps in the development of three major ectodermal appendages

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Cite this page: Hill, M.A. (2014) Embryology Lecture - Integumentary Development. Retrieved July 22, 2014, from //php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Integumentary_Development

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