Development and function of skin Flashcards
What are the functions of the skin?
- protection (mechanical, chemical, biological)
- temperature regulation
- reception of stimuli
- secretion
- immune response
- vitamin D synthesis
- pigmentation for communication/sexual attraction, camouflage, etc.
What are the stages of embryotic development of the skin?
1) Specification
2) Morphogenesis
3) Differentiation
What is specification?
- occurs during the embryotic period
- process in which the ectoderm lateral to the neural plate is committed to become epidermis and the subsets of the mesenchymal and neural crest cells are committed to for the dermis
- determined by multiple factors such as Hox and TBox (TBx)
What is morphogenesis?
- occurs during the early fetal period
- process in which the tissues committed during specification begin to form their specialized structures including epidermal stratification, appendage formation, subdivision between dermis and subcutis, and vascular formation
What is differentiation?
- occurs during the late fetal period
- process by which the tissues that began to specialize during morphogenesis continue to develop and become their mature forms
Describe gastrulation
- Early developmental process in which an embryo transforms from a one-dimensional layer of epithelial cells, a blastula, and reorganizes into a multilayered and multidimensional structure called the gastrula
- Involution and cell redistribution results in 3 embryonic germ layers (ectoderm, mesoderm, and endoderm). Ectoderm then further subdivides into the neuroectoderm and presumptive epidermis under the influence of bone morphogenic proteins (BMPs) which will also help with Engrailed-1 to specify volar vs interfollicular skin as well as Wnt and Fgf
Describe what happens during step 1 of epidermal development (specification)
- Shortly after neurulation, ectodermal cells form periderm and basal layer
- This epidermis covering the embryo initially consists of a single layer of cuboidal cells resting on a basal lamina
How does the epidermis formed during stage 1 of epidermal development compare to the fully developed epidermis?
- Differs from later versions because the cells are more columnar and have not formed hemidesmosomes (attachment between cells seems to be mediated by E- and P-cadherin) and the integrins (α6β4) are not localized to the basal pole
- Express keratins K8/18 at first but express K5/14 by the end of specification
Describe periderm cells
- From after neurulation from ectodermal cells during stage 1 of epidermal development
- Periderm cells form “pavement epithelium” and are involved in the exchange of nutrients
- Connections between cells are sealed with tight juntions
- Express K5, K14, and simple epithelia keratins K8, K18, and K19
- Eventually undergo apoptosis and are shed during morphogenesis and differentiation
Describe what happens during step 2 of epidermal development (morphogenesis)
- Epidermis begins stratification and formation of an intermediate layer
- Happens during early fetal development (when hematopoesis switches from yolk sac to bone marrow)
- Cells in the new intermediate layer are similar to mature spinous lay and express K1/K10 and desmoglein-3
- Basal layer becomes more cuboidal and begins to express K6, K8, K19, and K6/16 (also expressed in hyperplastic tissue)
- Basal layer begins to make hemidesmosome anchoring proteins (BPAG1, BPAG2, collagen V and collagen VII)
What does the expression of the p63 gene do?
- Expression of p63 gene plays a critical role in proliferation and maintenance of the basal cell layer
- Mutations in this lead to ankloplepharon, ectodermal dysplasia, ectrodactyly, cleft lip/palate, and nail development
Which factors regulate basal cell growth during morphogenesis?
Notch, p63, keratinocyte growth factor Fgf-7 (made by the dermis)
At what stage of epidermal development do hemidesmosomes begin to form?
Morphogenesis (finish during differentiation)
Describe what happens during step 3 of epidermal development (differentiation)
- Occurs during the late fetal period
- The periderm is sloughed
- Stratum granulosum and stratum corneum layers are formed
- Basal cells correctly express hemidesmosomal proteins plectin and α6β4 integrin (now localized to basal pole)
- Problems that happen at this point lead to bullous genodermatoses
- More superficial cells undergo further terminal differentiation and express the keratin aggregating protein fillagrin
- Formation of the cornified envelope is a late feature and relies on transglutaminase, LEKT1 (encoded by SPINK-5), phytanoyl coenzyme A, fatty aldehyde dehydrogenase, and steroid sulfatase to create a more mature lipid barrier
What does formation of the cornified envelope rely on?
- transglutaminase
- LEKT1 (encoded by SPINK-5)
- phytanoyl coenzyme A
- fatty aldehyde dehydrogenase
- steroid sulfatase
What are the primary specialized cells of the epidermis and when do they occur in epidermal development?
- Melanocytes
- Langerhans cells
- Merkel cells
- All are present by the end of the embryonic period (end of specification)
Describe melanocytes
- Cells that make melanin
- Derived from neural crest cells during the period of epidermal proliferation
- Express integrin receptors to migrate
- Depend on cell surface tyrosine kinase receptor as well as c-kit and its ligand stem cell factor to migrate, colonize, proliferate, and survive
- Melanoblasts migrate through mesenchyme to the basal layer of the epithelium where they become melanocytes
- A couple of months after melanocytes are detectable they begin to transfer pigment to keratinocytes
- Melanin is stored intracellularly as melanosomes which are moved to the tips of the dendritic processes where they are transferred to adjacent keratinocytes through a process known as cytocrine secretion
- In the adult there is roughly 1 melanocyte to 10 keratinocytes
What is pigment mosaicism?
- Patterned hypo- and/or hyperpigmentation that results from genetic heterogeneity of skin cells
- Most common clinical patterns are streaks and swirls following Blaschko’s lines in narrow or broad bands and a block-like distribution
- May reflect migratory pattern or failure of transfer of pigment
Describe Langerhans cells
- Cells that are residents of the epidermis and act as antigen presenting cells for T-lymphocytes as a peripheral component fo the immune system
- Derived from bone marrow and are of the monocyte-macrophage lineage
- Are present in the epidermis from an early stage in embryotic development
- Begin to express CD1 and produce Birbeck granules (in some species) by the embryotic-fetal transition
- Most numerous in the stratum spinosum
Describe Merkel cells
- Cells that function as sensory cells through interaction with free nerve endings to detect tactile stimuli and changes in contact pressure
- may originate from epidermal ectoderm or migrate from the neural crest
- Reside in the basal layer of the epidermis and can be seen on histopath
Describe the development of the dermis
- Develops during the late embryonic period with diverse origins including mesencymal cells from dermatomal cells and somatopleural mesoderm depending on the body site
- The dermal mesencyme of the face and anterior scale is from neural crest ectoderm
- Limb and ventral body wall mesenchyme are from lateral plate mesoderm
- Dorsal body wall mesenchyme is from dermomyotomes of the embryotic somite (also originally mesodermal)
- By the embryonic-fetal transition the superficial mesenchyme becomes distinct from the underlying tissue; the reticular dermis begins to take on classic fibrillar appearance while the papillary dermis is more woven, large collagen and elastin fibers begin to accumulate in the reticular dermis
- By the end of the second trimester in humans the dermis becomes capable of scarring
- The dermis continues to become thicker and more organized through the fetal period until at birth it resembles the adult dermis but is still cellular
The epidermis derives from which layer of the gastrula?
Ectoderm
The dermis mainly derives from which layer of the gastrula?
Mesoderm (except face and scale has neural crest ectodermal origin)
Which factors are important to specification of the dorsal limb?
- LIM homeobox transcription factor 1β (Lmx1)
- Wnt7a
Which factors are important to specification of ventral limb mesenchyme?
- En1
-BMPs
Describe the structure of the mature dermis
- There are dermal papillae which project into the epidermis and are comprised of loose connective tissue
- The underlying reticular layer has dense irregular connective tissue which is a complex meshwork of collagen and elastin fibers in proteoglycans
How does the embryonic dermis differ from the mature dermis?
- The embryonic dermis is cellular and amorphous with few organized fibers
- There are a large variety of pluripotent cells in a hydrated gel that is rich in hyaluronic acid (these cells are thought to be progenitors of cartilage-producing cells, adipose tissue, dermal fibroblasts, and intramembranous bone)
- The embryonic dermal fibers are fine filaments but not the thick fibers of the mature dermis
- The protein components of elastin and collagen are made/present in the embryonic dermis but are assembled
- There is no obvious separation between the cells that will become musculoskeletal and the mature dermis
- Is non-scarring
- Mostly contains type I collagen
Describe proteus syndrome
- There are focal defects in multiple tissues
- Is probably genetic mosacism affecting genes in the embryonic dermis cause by AKT1 associated activating mutations
- Diffuse mutations would be fatal
What are the diseases that occur when something goes wrong in the development of the dermis during the embryonic-fetal transition?
- *Dystrophic EB (collagen VII defect)
- *Marfan syndrome (fibrillin defect)
- *Ehlers-Danlos (collagen V)
- *Cutis laxa (elastin)
- *Osteogenesis imperfecta
- PXE
- Hereditary hemorrhagic telangiectasia
When in do the cutaneous blood vessels form?
- Early gestation
- But do not mature until a few months after birth in mammals
What are the names of the 3 parallel skin networks in the dermis?
- Subcutaneous plexus: derived from arterial branches to superficial cutaneous structures
- Cutaneous plexus: supplies hair follicles and sweat glands, arises from branches of subcutaneous
- Superficial plexus: supplies papillary processes, arises from branches of the cutaneous
How does the epidermis gets its nutrients?
Diffusion from capillary loops in the papillary processes of the dermis
Describe the origin of the lymphatics
- Likely from endothelia cells that bud of of veins
- The pattern of lymph vessels develop parallel to the blood vessels
- LYVE-1 and Prox-1 genes are critical for the earliest lymphatic specification
- VEGF-R3 and SLC are important for later differentiation
Briefly describe cutaneous nerves
- Develop parallel that of the vascular system for pattern, maturation, and organization
- Consist of somatic sensory and sympathetic autonomic fibers which are predominantly small and unmyelinated
- There are a variety of nerve endings which are more numerous in hairless areas
- Sensory fibers are predominant in the dermis and hypodermis but extend to external root sheath and deep epidermis
- Can be divided into free nerve endings (primarily in the epidermis for pain and thermoreception) and encapsulated nerve endings (in dermis and hypodermis for mechanoreception
Briefly describe the structure, function, and development of the subcutis/hypodermis
- Under the dermis the mesenchyme forms a layer of loose connective tissue with irregular bundles of collagen interspersed with elastic fibers and adipocytes that anchors the skin to the underlying tissue
- Is not present in lips, cheeks, eyelids, ears, and anus
- Varies in nature and depth in location and species (is less dense with more elastic fibers in carnivores and sheep, is very thick and dense in pigs, is thin in other ungulates)
- Development starts in the end of the first trimester
- By the end of the second trimester adipocyte precursors differentiate and accumulate lipids under the influence of leptin and peroxisomes
- By the third trimester, fat lobules are present and fibrous septae separate mature adipocytes
Which major proteins are present in the earliest version of the basement membrane?
- Laminin 1
- Collagen IV
- Heparin sulfate
- PGs
Which proteins are expressed early on in the development of the skin but are not localized to the basal poles until the hemidesmosomes form?
α6β4 integrins
Which of anchoring filaments and fibrils assemble when the hemidesmosome begins to form?
- Laminin-332 (an anchoring filament)
- Collagen VII (an anchoring fibril)
At what stage are all components of the basement membrane present?
Late embryonic development
What are the two components that lead to the development of skin appendages?
1) the epidermal portion that produces the differentiated product
2) the dermal component which regulates differentiation (the signals from the underlying mesoderm)
The expression of which genes specify the location of the developing skin appendage?
- Hox
- T-box
When/where on the body do the skin appendages begin to form?
- The early fetal period when the epidermis is 3 layers
- Slight elevations around the lips, cheeks, and lower jaw of the fetus are the first macroscopic evidence
What is the dermal signal that tells the basal cells of the epidermis to form the follicular placode?
B-catenin
What is the follicular placode?
The first step in hair follicle development when the basal cells of the epidermis clump at regular intervals on the scalp under the influence of the dermal signal B-catenin
Which promoters and inhibitors play a role in the signaling when the follicular placode induces the dermis to form ‘dermal condensates’?
- Wnt
- Ectodysplasin (Eda)
- Edar (the receptor of Eda)
- BMP
- Shh
- Noggin
- Follistatin
What embryonic layer does the nervous system arise from?
Ectoderm (neural crest cells)
What does Wnt do during the development of the skin appendages?
- Generally considered the first dermal signals
- Activate Eda/Edar
- The hair peg sends Eda and Wnt signals which contribute to the initial hair bud formation
What are the canonical Wnt signaling pathways?
B-catenin-dependent Wnt signaling (Wnt/b-catenin signaling) which is known as an important regulatory pathway that governs developmental processes and fate choices during tissue morphogenesis
What are the non-canonical Wnt signaling pathways and what do they generally do?
Wnt-activated signaling pathways that do not depend on b-catenin are referred as non-canonical Wnt pathways and also play divergent roles in development and cancer
What do Eda/Edar do during the development of skin appendages?
- Ectodysplasin (Eda) is a Tnf family ligand that is confined to ectoderm)
- Edar is the receptor of Eda
- They bind and then inhibit BMP/induce Shh
- The hair peg sends Eda and Wnt signals which contribute to the initial hair bud formation
What does Shh do during the development of skin appendages?
- Sonic hedgehog induces aggregation of mesencymal cells and promotes the development of individual hair follicles
What does BMP do during the development of skin appendages?
- In conjunction with DKK-4, BMP suppresses follicle development in the dermis immediately next to existing hair follicle primodium thereby regulating spacing