Embryology 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 (non-keratinocyte cells) of the epidermis and when do they occur in epidermal development?
- Melanocytes
- Langerhans cells
- Merkel cells
- All are present by the end of specification
Describe melanocytes
- Cells that make melanin
- Derived from neural crest cells
- 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 from mesencymal cells
–> except face is from neural crest ectoderm - By the end of the second trimester in humans the dermis becomes capable of scarring (Col III -> I)
- 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 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
- Superficial dermis is comprised of loose connective tissue
- Deep dermis 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?
- Cellular and amorphous with few organized fibers
- Pluripotent cells in a hydrated gel rich in hyaluronic acid
- Embryonic dermal fibers are fine filaments, not the thick fibers of the mature dermis
- Components of elastin and collagen are present but are not assembled
- No obvious separation between the cells 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 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 vacular 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 development and variation in structure between species of the subcutis/hypodermis.
- 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
–> less dense, more elastic fibers in carnivores and sheep
–> very thick and dense in pigs
–> thin in other ungulates
Which major proteins are present in the earliest version of the basement membrane?
- Laminin
- Collagen IV
- PGs (heparin sulfate)
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 in 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/b-catenin
- Eda/Edar
- 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 signal
- 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?
- 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
What does DKK-4 do during the development of skin appendages?
- DKK-4 is a Wnt inhibitor
- In conjunction with BMP, it suppresses follicle development in the dermis immediately next to existing hair follicle primodium thereby regulating spacing
What does Noggin do during the development of skin appendages?
It is expressed in combination with follistatin in the follicular placode region and together they inhibit BMP to make sure the follicle continues to form in this location
What does follistatin do during the development of skin appendages?
It is expressed in combination with Noggin in the follicular placode region and together they inhibit BMP to make sure the follicle continues to form in this location
What are the 3 broad stages of mammalian hair follicle development?
1) hair placode formation
2) hair follicle organogenesis
3) cytodifferentiation
What happens in stage 0 (of 8) of hair follicle development?
A single basal layer of mulitpotent epithelial cells is developed
What happens in stage 1 (of 8) of hair follicle development?
- Continual interactions between the mesenchymal cells and the epithelium result in the formation of follicular placodes
- 1st mesenchymal/dermal signal = “make appendage”
- Primarily is under the influence of B-catetin then Wnt then Eda/Edar
What happens in stage 2 (of 8) of hair follicle development?
- The hair placode elongates downwards towards the dermis while the dermal fibroblasts that have aggregated under the placode condense and become more evident
What happens in stage 3 (of 8) of hair follicle development?
-Proliferations of the basal layer of the epidermis project into the mesenchyme, forming hair buds or pegs primarily mediated by platelet derived growth factor-α (PDGF-α) and Shh
- The hair peg extends into the skin at an oblique angle
- Aggregated dermal fibroblasts form a spherical dermal papilla adjacent to the hair peg
What happens in stage 4 (of 8) of hair follicle development?
- The hair peg thickens at the lower end to for a pair bulb, half enclosing the elongated dermal papilla (like an inverted cup to form the hair bulb)
- The germinal matrix forms above/around the dermal papilla (some sources refer to this as an epithelial root sheath and others as an inner root sheath)
What happens in stage 5 (of 8) of hair follicle development?
The inner root sheath extends up the hair follicle and the bulge becomes visible
What happens in stage 6 (of 8) of hair follicle development?
- The downward growth of the hair follicle reaches the subcutis
- The inner root sheath forms a hair shaft at the upper end
- The dermal papilla becomes thinner and is fully enclosed
- The sebaceous gland begins to form
What happens in stage 7 (of 8) of hair follicle development?
The tip of the hair shaft leaves the inner root sheath and enters the hair canal
What happens in stage 8 (of 8) of hair follicle development?
The hair shaft reaches reaches and protrudes above the skin surface
During the bulbous hair peg stage, the developing hair has three bulges along the connective tissue sheath. What do these go on to form?
- The lowest develops first and a small band of smooth muscle from mesenchymal cells in the dermis connects to this and forms the arrector pili muscles, also contains multipotent hair stems cells in humans
- The middle bulge becomes the sebaceous glands
- The small uppermost bulges form the sweat glands (primarily apocrine in animals)
Which hairs develop first in fetal development?
Sinus hairs
When do compound hairs develop in development?
Post-natal
How do sinus hairs develop?
- Development is initially similar to primary hairs
- But then the follicular bud enlarges and goes deeper into the hypodermis
- They develop a blood-filled sinus which separates the dermal connective tissue sheath into an inner and outer sheath (ruminants and horses also have trabeculae in between)
A) Ectoderm
B) Endoderm
C) Mesoderm
Briefly describe the development of the mammalian sebaceous gland.
- Arise as lateral outgrowth of the basal epithelium of the developing follicle deep to the sweat glands
- Usually develop later than the sweat glands
- Mature over the course of follicular development (accelerated during second and third trimesters due to maternal steroids)
- Start as pear-shaped lobular structures with clusters of acini opening into a short, wide duct
- The outer proliferative cells of the gland give rise to the differentiate cells
- With repeated mitotic division the small basal cells give rise to cells that migrate and fill the acinar lumen
- As those cells enlarge they accumulate lipid droplets and the nuclei become pyknotic
- Sebum is discharged into the lumen of the hair follicles
What is holocrine secretion?
- Holocrine secretions are produced in the cytoplasm of the cell and released by the rupture of the plasma membrane, which destroys the cell and results in the secretion of the product into the lumen
- Mature cell dies and becomes the secretion
What is merocrine secretion?
- The gland releases small secretory granules and no part of the gland is lost or damaged
- Most common form of glandular secretion
- Also referred to as eccrine
How do eccrine aka atricial glands develop?
They arise from the ectodermal ridge and in humans they begin as mesenchymal pads on volar hands and feet
Merocrine secretion
Holocrine secretion
What is apocrine secretion?
- Secretory cells accumulate material at their apical ends, often forming blebs or “snouts”, and this material then buds off from the cells, forming extracellular vesicles
- But “apocrine” sweat glands seems to really use eccrine secretion!
Apocrine
How do apocrine sweat glands aka epitrichial develop?
-Start as nodular outgrowths of the basal layer of the epithelium of the hair follicle
- The dense cellular proliferation extends into connective tissue so the base of the gland may be deep to the hair bulb
- After formation of the lumen, the gland is lined by a double layer of cells so the inner layer forms the secretory acini and the outer layer differentiates into myoepithelial cells between the secretory and basal lamina
What signals mediate the differentiation of apocrine aka epitrichial sweat glands?
- Initiated by Wnt (Wnt10b)/B-catenin
- Then is modulated by DKK-4
- Then Eda/Edar is needed for formation
Describe nail development in humans.
- Presumptive nail structures develop on dorsal digit just prior to follicular development
- First sign is delineation if flat surface on nail bed
- A portion of the ectoderm then buds inward from the proximal boundary to make proximal nail fold
- Presumptive nail matrix cells are present on the ventral side of the proximal invagination
- Dorsal nail surface keratinizes and covers the nail bed
What is the primary function of Wnt7a?
- Dorsal limb patterning and therefore nail development
What role does Shh play in nail development?
None
What are the functions of LMX1b and MSX1?
Hair follicle and nail formation
What is Hoxc13?
A homeodomain-containing gene for follicles and nails
How does avian skin differ from mammalian skin?
- Is poorly keratinized with fewer epidermal layers
- Avian dermis has superficial loose layer and a dense coarse layer
What is the uropygial gland?
- Is located at the base of the tail in birds
- Is similar to sebaceous glands
- Makes an oily secretion which is spread during preening
- Gland is drained by two ducts that open onto the skin with a single papilla
- Well developed in aquatic birds and absent in some other species (ostrich, pigeon, parrot, and woodpecker)
What are the functions of feathers?
- Maintain body temperature
- Reduce water loss
- Communication for social behaviors and sexual attraction
- Flight/movement
How does the follicle bulge differ in humans and mice vs dogs and cats?
- In humans and mice they are presumed to be sites of epidermal and hair follicle stem cells
- They are absent/there are just sites of arrector pili attachment in dogs and cats
Dystrophic EB is a defect in what?
Collagen VII
Marfan syndrome is a defect in what?
fibrillin
Ehlers-Danlos is a defect in what?
collagen V
Cutis laxa is a defect in what?
elastin
What is the mitosis stage of the eukaryotic cell cycle?
Last stage (4th)
Shortest (1-2 hr)
Cell divides and produces daughter cells (cytokinesis)
What is the Gap 1 stage of the eukaryotic cell cycle?
1st stage
Longest but most variable in duration
- May enter G0 (rest) instead of continuing
Cellular contents (excluding chromosomes) are duplicated
What is the S stage of the eukaryotic cell cycle?
2nd stage
Lasts 7-16 hours in keratinocytes
DNA (chromosomes) are duplicated
What is the Gap 2 stage of the eukaryotic cell cycle?
3rd stage
Lasts 6-8 hours
- May enter G0 (rest) instead of continuing
Cell “double checks” for errors and makes repairs
What is the normal mitotic index of the basal layer?
5% (if count cells in M phase)
What is “turn over time” in the context of cell replication?
Amt of time required to replace cells in a particular compartment
