Structure and Function of the Skin Flashcards
_________ are a gene family critical for normal embryologic development; they likely play a very important role in development of skin adenexa, pigment system, and stratified epithelium during embryogenesis.
Homeobox (hox) genes
What are the three layers of the ectodermal covering?
- The basal layer (stratum germinativum)
- The outer layer (periderm)
- Then 3 layers forms in between the two layers (stratum intermedium)
Dermal development is characterized by an _____ in thickness and number of fibers, a decrease in ground substance, and the transition of ____ cells to _______.
increase
mesenchymal cells to fibroblasts.
Fetal skin contains a large percentage of type____ collagen compared with the skin of an adult, which contains a large proportion of type ____collagen.
III
I
Embryonal stratum germinativum differentiates into hair germs (primary epithelial germs) that give rise to what three structures?
hair follicles, sebaceous glands, and epitrichial (apocrine) sweat glands.
The epidermal placode develops into what three epithelial cylinders?
Innermost = hair shaft
Outermost cylinder = outer root sheath (ORS)
Middle = inner root sheath
As the hair peg lengthens, and develops into a hair follicle and hair, list the three bulges that appear?
Lowest (deepest) = develops into the attachment for the arrector pili muscle
Middle = develops into the sebaceous gland
Uppermost = develops into the epitrichial sweat gland
Secondary hairs develop on the caudal or cranial side of the primary hair follicle.
caudal
What are the six major morphogenic family systems have been recognized to be important
Genes of the Hox cluster
Fibroblast growth factor (FGF)
Transforming growth factor (TGF-B)
Sonic hedgehog (shh)
Wingless or wnt pathway
Neurotrophins
What is a marker of early anagen hair follicles and it is important in the protein cross-linking that contributes to the shape and strength of hair?
Transglutaminase
The diameter of the hair shaft is determined by the volume of ______, and the length of the hair shaft is determined by both the rate of the hair growth and duration of the anagen.
the hair matrix epithelium
The hairs of the cat have been divided into three types based on the gross appearance:
Guard hairs (thickest, straight, evenly tapered to a fine tip). Awn hairs (thinner, possessing subapical swelling below the hair tip). Down hairs (thinnest, evenly crimped or undulating.)
***The secondary hairs of the cat are far more numerous than primary***
All hair follicles grow in what direction in relation to the epidermis?
obliquely (30-60 degrees)
During what phase of the hair cycle do large numbers of keratinocytes in the outer root sheath undergo apoptosis and the epithelial strand regress?
catagen
_____ are thought to play a fundamental role in induction of epithelial differentiation. They are the primary target cells that respond to hormones and mediate growth-stimulating signals to the follicular epithelial cells.
Dermal papilla cells (mesenchymal component of hair bulb)
Alterations in ____ that control hair follicle structure result in follicular dysplasia.
morphogens
What is the normal coat comprised of?
The normal coat is see in the GSD, Welsh Corgi and wild dogs. It is composed of primary hairs (course guard hairs or bristles) and secondary hairs (fine hairs or undercoat).
What are the reported ultrastructural changes reported in non-lesional AD skin?
Widening of the intercellular spaces, retention of lamellar bodies in the corneocytes and irregularities and fragmentation of lipid lamellae.
Similar to humans with AD
Colonization of staphylococcus sp can result in an increase in ____ and ____ from cutaneous T-cells. This increase in ___ can induce the production of fibronectin, which increases the adherence of staph to keratinocytes.
IL-4/IL-13
IL-4
***Dupulimab binds to the alpha subunit which is shared by IL-13***
Colonization by Staph spp. further damages atopic skin as bacteria produce ______ and _____, which additionally decrease ceramides in the SC.
ceramidases and proteases
What gene family encodes information critical for normal embryologic development of skin adenexa, pigment system and stratified epithelium during embryogenesis?
Homeobox (Hox) genes
Encode a sequence of 60 amino acids that bind to DNA and regulate transcription (expression of genes into proteins)
Embryonic skin consists of a single layer of _____ cells and a dermis containing loosely arranged _____ cells embedded in an interstitial ground substance.
ectodermal
mesenchymal
Melanocytes (neutral crest origin) and Langerhans cells (bone marrow origin) become identifiable during what period of embryonic maturation?
ectodermal
Dermal development is characterized by an increase in thickness and number of fibers, a decrease in ____ and a transition of mesenchymal cells to _____.
ground substance
fibroblasts
Fetal skin contains a large percentage of type ___ collagen compared to the skin of adults which contains a large amount of type ___ collagen.
III
I
The embryonal stratum germinativum differentiates into hair germs (primary epithelial germs) that give rise to ____, _____ and _____.
hair follicles
sebaceous glands
apocrine glands
Hair germs initially consist of an area of crowding or deeply basophilic cells in the basal layer of the epidermis. The areas of crowding becomes buds known as______ that protrude into the dermis. Each bud lies a group of mesencymal cells, referred to as _____ from which the dermal papilla is later formed.
epidermal placodes
dermal condensate
What three epithelial cylinders develop from the dermal placode?
innermost = hair shaft middle = IRS outermost = ORS
As the hair peg lengthens and develops into a hair follicle and hair, three bulges appear? What are the three bulges and what do they develop into?
The lowest (deepest) of the bulges develops into the attachment for the arrector pili muscle; the middle bulge differentiates into the sebaceous glands and the uppermost bulge evolves into the epitrichial sweat gland. These appendages develop on the cranial side of primary hair follicles; secondary hair follicles develop on the caudal side.
Where do first hairs appear on the fetus?
vibrissae and tactile or sinus hairs that develop on chin, eyebrows and upper lip as slightly raised dots.
At birth, the majority of hair follicles or dogs are ____ ones; ______ develop caudal to the primary hairs during the first 12- 28 weeks of life.
primary
secondary follicles
_____ are substances that control hair follicle development.
morphogens
The skin, hair and subcutis of a newborn puppy represent XX% of its body weight, these structures represent approximately XX% of body weight
24
12
The pH of normal canine skin is ranges from __ to __.
4.84 - 9.95
What enzyme is a marker of early anagen hair follicles, and it is important in the protein cross-linking that contributes to the shape and remarkable physical strength of hairs?
Transglutaminase
What are the known growth factors involved in hair follicle induction?
EGF, TGFB1, TGFB2, neurotrophic 3. These growth factors control cellular proliferation and collagenase release from cultured hair follicles.
What cell types are involved in the regulation of hair growth, especially during catagen phase?
Interplay between MHC I, chondroitin proteoglycans and activated macrophages.
What are intrinsic factors involved in hair cycle?
growth factors, cytokines, dermal papilla, inflammatory cells int he immediate environment
The hair cycle and haricot are also affected by hormonal changes. In general, anagen is initiated and advanced by _____ and ____ hormone. Excessive amounts of ____ or ____ inhibit anagen and suppress hair growth rate.
Thyroid, Growth
GC, estrogens
____ cells, which are mesenchymal component of the hair bulb, are considered to play a fundamental role in the induction of epithelial differentiation.
Dermal papilla, These cells are morphologically and functionally differentiated from dermal fibroblasts and are thought to be the primary target cells that respond to hormones and mediate growth-stimulating signals to the follicular epithelial cells.
What is a ‘normal coat’?
Typified by that seen in GSD, Corgi and wild dogs.
It is composed of primary hairs (course guard hairs or bristles) and secondary hairs (fine hairs or undercoat).
What is a ‘short’ coat?
The coarse short coat is typified by the Rottweiler and many of the terriers. This type of coat has a strong forth of primary hairs and a much lesser growth of secondary hairs.
The fine short coat is exemplified by the boxer, dacshunds, and miniature pinchers. This type of coat has the largest number of hairs per uint area. the secondary hairs are numerous and well developed, and the primary hairs are reduced in size compare dot those of the normal coat.
What is the ‘long coat’?
The long coat can also be arranged into two subdivisions: the fine long coat and the woolly or course long coat. The fine long coat is found int he cocker spaniel, the Pomeranian and the chow chow.
The woolly or course long coat is found in the Poodle, Bedlington terrier and Kerry blue terrier.
Secondary hairs make up 70% of the total weight of these coats.
Describe the classic ‘agouti-type’ hair
Ex are the GSD and Norwegian Elkhound
The tip is white or light, the heavy body is pigmented brown or black, and the base is a light yellow or red-brown.
Pigment cells in the bulb or the hair deposit pigment in or between the cortical and medullary hair cells.
The black-brown pigment is _____; yellow-red pigment is called _____.
eumelanin
pheomelanin
Activation of melanocortin 1 receptors (MCR1 gene) on melanocytes leads to production of ______; inhibition or MCR1 results in the production of _____.
eumelanin
pheomelanin
What gene controls the shade of eumelanin?
Tyrosine related protein gene 1 (TYRP-1)
The generally recognized gene series involved in the coat color of dogs are called A, B, C, D, E, G, H, I, K, M, P, R, S and T.
- Agouti (ASIP)
- brown (TYRP1)
- C (colored/albino)
- D (blue dilution, melanophilin (MLPH)
- extension (MC1R)
- G (graying)
- H (Harlequin)
- I (phaeomelanin dilution)
- K (black, beta0defensin 103)
- M (merle, SILV)
- P (dilute)
- S (spotting, microphthalmia-associated transcription factor, MITF)
- T (ticking)
What does the ‘tabby’ coloration consist of?
The underlying pattern is agouti - characterized by hairs with a blueish base and a black tip separated by yellow banding.
The tabby genes determine whether the cat has narrow, vertical, gently curving stripes (mackerel), larger patches (blotch) or Abyssinian pattern.
How does temperature play a role in ‘tipped hair coats’?
Pointed hair coats are characterized by pale-colored hair not he body with darker hairs on the extremities or points. Points drive through a temperature-dependent enzyme that converts melanin precursors into melanin by the process of oxidation. Higher temperatures = lighter hair.
Inflammation and hyperemia result in more lightly colored new hair.
Expression of this gene is C, tyrosinase gene, TYR
What gene determines the multicolored coats in tortoiseshell and piebald spotting patterns?
White gloves gene (KIT)
What gene dilutes black to blue (gray), orange to cream, and seal-point ti blue-point (Siamese) AND is inherited as an autosomal recessive trait?
The dilution gene, melanophilin, MLPH
What is the difference between Cornish Rex and Devon Rex?
The Cornish Rex lacks primary hairs; The Devon Rex has primary hairs that resemble secondary hairs with absent or stubbled whiskers.
What are the boundaries of the areas of distribution of the main cutaneous nerve stems?
Voight lines
What lines reflect the course of blood vessels or lymphatics?
Langer lines
What lines form the pattern assumed by many different nevoid and acquired skin diseases?
Blashko Lines
These lines reflect a mosaic condition deriving either from a single mutated clone of cells originating from a post zygotic mutation or from an X-linked mutation made evident by lyonization.
What are the FOUR distinct cell types within the epidermis?
keratinocytes, melanocytes, Langerhan cells, and Merkel cells.
What layer of the epidermis consists of cuboidal to columnar cells resting on the basement membrane zone that separates the epidermis from the dermis?
Basal layer, most of these cells are keratinocytes that are constantly reproducing and pushing upward to replenish the epidermal cells above,
Cells of the stratum basale contain K5 and K14 keratin filaments.
What major cell adhesion molecule provides an anchor for keratin filaments connecting the nuclear envelop to the cell membrane and also anchors adjacent cells together to stabilize the structure of the epidermis?
Desmosomes
What are the three major gene families the molecular components of desmosomes belong to?
plakins (desmoplakin)
armadillo proteins (plakophilin, plakoglobin)
cadherins (desmogleins, desmocollins)
What structures are junctional complexes distributed along the inner aspect of basal keratinocytes; their major role is epidermal-dermal adhesion.
hemidesmosomes
What structures are a large family of cell surface adhesive receptors. These cell surface glycoproteins are important in cell-cell and cell-matrix interactions, and also act as signal transducers through which extracellular and intracellular compartments can influence and modify each other?
Integrins
Each intern consists of a heterodimer of an a and b subunit which are noncovalently associated. In the epidermis, integral expression is confined to the basal layer.
Which integrins are most abundant in the epidermis?
a2, a3,b1,a6 and b4
a5b1 function?
mediates keratinocyte adhesion to fibronectin
a2b1 function?
mediates keratinocyte adhesion to collagens type 1 and type iV and laminin
a3b1 function?
receptor for epiligrin and is involved in adhesion to laminin
a1b5 function?
mediates keratinocyte adhesion to vitronectin
a6b4 function?
mediates keratinocyte adhesion to laminin
What layer of the epidermis is composed of daughter cells from the stratum basale?
Stratum Spinosum
What are the four major types of adhesive and communicative structures the mediate keratinocyte adhesion?
desmosomes, hemidesmosomes, adherens junctions and focal adhesions,
What structures serve primarily as intercellular route of chemical communication?
gap junctions
What are the three types of cytoplasmic filaments that make up the keratinocyte cytoskeleton?
cytokeratin
actin
microtubules (tubulin)
_____ and _____ are crucial for desmosome and hemidesmosome formation.
calcium and calmodulin
What three keratinocyte derived calmodulin-binding proteins participate in a flip-flop regulation of calcium-calmodulin interactions?
caldesmon, desmocalmin and spectrin
All epithelia express a keratin pair; which oncists of what structures?
One keratin chain from the acidic subfamily (type 1 keratin, cytokeratins 9-20) and one chain from the neutral-basic subfamily (type II keratins, cytokeratins 1-8).
What keratins make up the spinous layer?
K1/K10 AND retain K5/14 synthesized in the basal layer
Keratinocytes of the stratum spinosum synthesize what products? These are secreted into the intercellular spaces of the stratum granulosu and are important in the barrier function of the epidermis.
synthesize lamellar granules (keratinosomes, membrane-coating granules, Odland bdies) which contain glycolipids, glycoproteins, phosholipids, free sterols, glucosylceramides and acid hydrolyses.
Keratinocytes in stratum spinosum synthesize lamellar granules (Odland bodies) which consist of what substances?
profillagrin, keratin filaments, loracrin
Where are keratohyalin granules synthesized?
Keratohyalin granules are synthesized in the stratum granulosum; however, they are not true granules because they lack a membrane and are more accurate described as insoluble aggregates.
What are profillagrin degradation productions?
urocanic acid, carboxylic acid, lactic acid; important for normal stratum corneum hydration and also help filter UV radiation.
What is a cysteine-rich protein synthesized in the stratum granulosum in association with keratinohyalin granules?
loracrin (synthesized in stratum granulosum) involved in binding keratin filaments together in the corneocyte and anchoring them to the cross-linked envelope.
What are the two morphologic forms of keratihyalin granules in the rodent?
The P-F granule - irregularly shaped and contains profillagrin; whereas, the L granule is smaller, rounded and contains loricrin.
What are the protein components of the CE?
lorcrin, involucrin, filaggrin, elfin, cystitis A, cornifelin, small proline-rich proteins and “late envelope” proteins
______ are a superfamily of enzymes that are important in apoptosis, keratinization and hair follicle formation.
Transglutaminases; keratinocytes and epidermal transglutaminase mediate the sequential cross-linking of the cornfield cell envelop precursor proteins.
Cheifly expressed in the stratum granulosum and upper stratum spinosum.
The most important product of the epidermis is ____; a highly stable disulfide condition-containing fibrous protein.
keratins
alpha - keratin = skin/hair
beta keratins - feathers/scale
What is the function of ornithine decarboxylase?
This enzyme is essential for biosynteisis of polyamides (putrescine, spermidine, and spermine); which encourage epidermal proliferation.
What are the four distinct cellular events in the process of cornification?
- keratinization - synthesis of the principle fibrous proteins of the keratinocytes
- keratohyaline synthesis - including the histidine-rich protein filaggrin
- formation of the highly cross-linked insoluble stratum corneum
- generation of neutral lipid-enriched intercellular domains resulting from the secretion of distinctive lamellar granules.
Where are lamellar bodies primarily synthesized?
keratinocytes in the stratum spinosum
What are amide-linked fatty acids containing a long-chain amino alcohol (spinchoid base).
ceramides; they are the most important lipid component for lamellar arrangement in the stratum corneum and barrier function.
Linoleic acid, an essential fatty acid for dogs and cats, found in which ceramides?
Ceramides 1, 4 and 9.
Which ceramides bind to involucrin and other proteins of the CE, forming a scaffold for the binding of tother lipids into intercellular lipid bilayer?
Cermides 1 and 2
______ play a crucial role plasticizing the horney layer to allow stretching and bending by fluidizing barrier lipids.
ceramides
What are transient amplifying cells?
Proliferating keratinocytes that have limited capacity for self renewal & will after a couple of divisions terminally differentiate
Both stem cells and amplifying cells lives in basal layer & lower spinous layer
Divide rapidly—have an avid uptake but short retention of thymidine
What are the three basal cell states?
- Holoclones: correspond to stem cells
Colonies of small, regular cells
Give rise to many other colonies
A single stem cell from holoclone can give rise to up to 4 million keratinocytes.
2.Meroclones: correspond to the transient amplifying cells
Produce colonies, but fewer in number than holoclones
Located in the basal and suprabasal layers
Provide the bulk of cell divisions needed for stable self-renewal
- Paraclones: correspond to differentiated, postmitotic cells; Undergo terminal differentiation
Yield only very small number of colonies
List characteristics of the basal cell layer?
Contains mitotically active, columnar shaped keratinocytes
Contain pigmented melanosomes transferred via phagocytosis from melanocytes
Attach via keratin filaments (K5 & K14) to basement membrane zone at hemidesmosomes
Also express K19 & 15
Attach to other surrounding cells through desmosomes
Major function: provided mechanical attachement to underlying basement membrane through hemidesmosomes & integrins
Desmosomes
Ca-dependent cell surface modifications that promote adhesion of epidermal cells and resistance to mechanical stress
Site where the metabolic barrier of the epidermis occurs
Most of the process of terminal differentiation is determined by ______ levels
Low calcium maintains keratinocytes in a high proliferation/low differentiation state
High calcium promotes terminal differentiation of keratinocytes
_____ promotes transition from spinous to granular layer cells
Protein kinase C
Recessive X-linked ichthyosis
mutation of steroid sulfatase
Results in retention hyperkeratosis
Profilaggrin
(F granules)
1st appearing in the granular layer & diffusely distributed w/n cytoplasm
Profliaggrin: large Ca binding phosphoprotiein of 10-12 repeating copies of filaggrin protein
Release from the keratohyalin granules results in a Ca2+ dependent cleavage (dephosphorylation & proteolysis) into filaggrin monomers
Occurs upon entering the transition zone between granular layer & stratum corneum
Filaggrin
aggregates with keratin to form macrofilaments
A cationic protein, rich in histidine residues
Function: an intermediate filament-associated protein, organizing & aggregating keratin into macrofibrils
Degraded into free amino acids & molecules including:
Urocanic acid & pyrrolidone carboxylic acid
Contribute to hydration of stratum corneum & help filter UV radiation
Mutation in Transglutaminase 1 gene
lamellar ichthyosis
Autosomal recessive condition characterized by large scales and disruption in the uppermost differentiating layers of the epidermis
Loricrin abnormalities lead to what two diseases in humans?
Vohwinkel syndrome with ichthyosis
progressive symmetric keratodermia
Clear Layer contains refractile droplets and a semifluid called what?
eleidin
Stratum lucidum, stratum conjunctum
Fully keratinized, compact, thin layer of dead cells
Anuclear, homogeneous, and hyaline-like
Differs histochemically from SC by being rich in protein-bound lipids
Best developed in food pads; less developed in nasal planum and absent in all other places
What layer of the epidermis is characterized by stacked layers of anucleate, flattened, eosinophilic cornified cells?
Stratum Corneum - Drastic remodeling occurs during the transition from granular cell layer to the stratum corneum
Formed by a two-compartment system of lipid-depleted, protein-enriched corneocytes surrounded by a continuous extracellular lipid matrix
Primary functions of the extracellular lipid matrix:
Regulation of permeability, desquamation, antimicrobial peptide activity, toxin exclusion, and selective chemical absorption
Primary functions of the corneocytes:
Mechanical reinforcement
hydration
cytokine-mediated initiation of inflammation
protection from UV damage
The cytoskeleton of all cells of mammals are composed of three filament system:
Microfilaments (6nm)
Intermediate filaments (8-10nm)
microtubules (25nm)
All intermediate filaments contain what 3 structures?
- Central α helical rod
- Conserved secondary structure
- Flanked by distinct amino head & carboxyl terminal end domains
Intermediate filaments are subdivided into what 6 groups based on tissue specificity and amino acid sequence?
Acidic type I——-epithelial keratin (9-23)
Basic type II—–epithelial keratin (1-8)
Type III: vimentin (mesenchymal cells), desmin (muscle), peripherin (peripheral nervous system), & glial fibrillary acidic protein (GFAP) (Glial cells and astrocytes)
Type IV: α-internexin (neurofilaments)
Type V: lamins (nucleus)
Type VI: nestin (stem cells of CNS and skeletal muscle)
What are the 3 types of cytoplasmic filament that keratinocyte cytoskeleton consists of?
Actin, microtubules and cytokeratin
Largest group of intermediate filaments
Keratins
Hallmark of all epithelial cells, including keratinocytes
Account for up to 85% of total protein of fully differentiated cells
Serve a predominately structural role in the cells
Describe Type 1 keratin filaments
Acidic
K9-K20
Describe Type 2 keratin filaments
Basic or neutral
K 1-8
Primary keratin structure
Two different chains assemble in pairs to create dimmers
Consist of an acidic & a basic keratin subunit
Composed of two α-helical chains oriented in a parallel & interwined in a coiled-coil rod formation
Describe formation of the cornified cell envelope
As intracellular Ca2+ levels rise in suprabasal cells, envoplakin, periplakin and involucrin are expressed (PIE) and fuse to the plasma membrane via the action of TG1 and 5 (calcium dependent)
Lamellar granules fuse to the plasma membrane then get lipid excretion into the intercellular space.
TG1 crosslinks ceramide to proteins
TG3 crosslinks Loricrin (most abundent) & SPR (small proline rich peptides) - Now PILES)
Where are intercellular lipids initially stored?
Intercellular skin lipids are initially stored in the lamellar granules which get extruded into the extracellular space in the upper granular layer during cornification
What is the precursor molecule to ceramides?
glucosylceramides (precursor to ceramides, dominant component of the stratum corneum lipids)
Where do lipids originate from?
Lipids originate in the Golgi apparatus & first seen in the upper spinous layer (abundant in the granular layer)
Lamellar granules fuse with the plasma membrane of keratinocytes & secrete their contents releasing stacks of membranous disks into the intercellular spaces
Role in synthesis & storage of cholesterol
Vital for normal adhesion & desquamation of cornified cells
Abnormal steroid and lipid metabolism
Recessive X-linked ichthyosis – mutation of steroid sulfatase
Results in retention hyperkeratosis
Phospholipids become _____ cholesterol becomes ____, & spingolipids become _____.
Phospholipids become free fatty acids, cholesterol becomes cholesterol esters, & spingolipids become ceramides.
**β glucocerebroside, acid sphingomyelinase & phospholipase A are involved in this modification***
List proteins in the cornfield envelope
- loricrin
- involucrin
- filaggrin
- elafin
- cystatin A
- cornifelin
- small proline rich proteins
- “late envelope proteins’
Trichohyalin
Significant component of the keratohyalin granules
Also part of the granular layer of the epidermis
Involucrin
Common component of the cornified envelope
Becomes cross-linked to other proteins and is thought to be part of the early component in the assembly of cornified envelope—scaffolding
Adjacent to the cell membrane & as the cell membrane becomes replaced, involucrin thought to be the preferred substrate to which external lipids (ceramides) are attached to the surface of the CE
Small Proline-rich proteins (SPRs)
Consist of a family of related small proline rich proteins
Serve as cross bridging proteins
The amount of SPR compared to Loricrin allows for the flexibility, rigidity or the toughness of a composite material (tissue)
Envoplakin
Expressed at desmosomal plaques
Homologous to desmoplakin
Link the CE to desmosomes and keratin filaments attachments for ceramides
Periplakin
Expressed along with envoplakin at desmosomal plaques
Serve as attachments for ceramides
Envoplakin & periplakin → heterotetramers.
Associate with the plasma membrane in a Ca2+ dependent manner
Profilaggrin
Formed initially in the granular layer & initially highly phosphorylated & accumulated in the keratohyaline granules
During cornification dephosphorylated & cleaved into filaggrin
Filaggrin
Becomes cross-linked to the epidermal CE & coordinates the structure of the cornified cells
Aggregates keratin intermediate filaments into tight bundles—this allows for the collapse of the cells
Filaggrin half life is 6 hours & degraded mostly into free amino acids
High concentration of hydrophilic a.a. is essential for the retention of water & contributes to the osmolarity &flexibility of the cornified layer
Three main functions of filaggrin?
- Alignment of the keratin intermediate filaments
- Controls cell shape (contracts)
- Maintenance of epidermal texture
Cystatin A
Keratolinin
Expressed in the spinous layer
Substrate for epidermal TGases & a minor component of the CE
Cysteine protease inhibitor - Might be relevant for the bacteriostatic properties of the skin
Elafin
SKALP; skin derived anti-leukopeptidase
A minor component of CE from normal adult epidermis
A potent inhibitor of elastase & proteinase 3
Highly expressed in wounded or psoriatic skin
Transglutaminases (TG)
Superfamily of Ca dependent enzymes important for apoptosis, keratinization, and hair follicle formation
Present in all stratified epithelia and hair follicles
Mainly expressed in the granular to upper spinous layers
Catalyze formation lysine bonds between proteins
Catalyze the covalent incorporation of biogenic polyamines into proteins
Transglutaminase I
Expressed primarily in keratinocytes
Membrane bound, processed form accounts for most of the activity in differentiating keratinocytes
Catalyzes cross-linking of involucrin at the plasma membrane & cornifin, elafin and the SPR proteins are added subsequently
Tranglutaminase 2
Vit A increases activity
Important role in would healing – involved in matrix repair & remodeling
Transglutaminase 3
cytoplasmic enzyme
Initially cross-links loricrin and SPRs together to form small interchain oligomers, which are then permanently affixed to the developing cornified cell envelope via further cross-linking by TGase1
Transglutaminase 5
Present in the upper epidermal layers (spinous & granular layers)
Induced in the early stages of keratinocyte differentiation
Can cross link Loricrin
Which enzymes are responsible for desquamation?
Acid phosphatase, Cathepsin-B, Carboxypeptidase, Sterol sulfatase
Corneocyte shedding/Desquamation
The final products of differentiation, the squames, finally reach the edge of the epidermis they are mummified remnants composed of cornified envelope surrounded by stacks of lipids packed with keratin macrofilament —Squames are then shed
The corneocytes are held together by ________
corneodesmosomes
Modified desmosomes structures
Located in the upper spinous and granular layers
Corneodesmosin
After transport and release from the lamellar bodies, corneodesmosin appears in the extracellular space & become associated with the desmosomal desmogleins & desmocollins
Corneodesmosin is cleaved by the stratum corneum ___ and ____ enzymes causing separation of adjacent corneocytes with cell shedding
tryptic and chymotryptic enzymes
Saturated FA
contain no carbon-carbon double bonds
Unsaturated FA
contain carbon-carbon double bonds
Polyunsaturated fatty acids (PUFAs)
Unsaturated fats with two or more double bonds
Cats are unique: lack _____, have limited ____ activity; unable to synthesize arachidonic acid – must obtain it from the diet
lack Δ-6-desaturase
Δ-5-desaturase
Mammals are unable to synthesize _____ and ______
linoleic acid or α-linolenic acid
Can make arachidonic acid from linoleic acid and eicosapentaenoic acid from α-linolenic acid
Essential fatty acid
a PUFA that cannot by synthesized by animals but is required for normal physiologic function
n-3 family
provided by the diet in green leafy veggies
Eicosapentaenoic acid can be obtained from marine fish oil
n-6 family
derived from veggies and present in seed oils (safflower & sunflower)
γ-Linolenic acid (product of linoleic acid) is found in seed oils of borage, evening primrose, & black currant
n-9 FAs
(oleic acid) – can ben synthesized de novo from acetyl coenzyme A by liver & tissue microsomes therefore is non-essential
EFA Deficiency
Causes renal & reproductive abnormalities, decreased growth rate, immunologic abnormalities, hypotrichosis, alopecia, scaling skin, weak cutaneous blood vessels and an increases tendency to bruise, decrease wound healing, sebaceous gland hypertrophy accompanied by increased sebum viscosity, and increased transepidermal water loss. Transdermal drug delivery systems use this intercellular lipid portion of the epidermis to allow penetration into the underlying dermis and vasculature
Arachidonic acid
most important of all of the EFAs; Fundamental component of cell membranes
Skin is unable to convert linoleic acid to AA; lacks Δ-6-DES & Δ-5-DES activity
Most AA is present in the phospholipids of the cell membrane
Major biologic function: parent to leukotrienes (LTs), prostaglandins (PGs), thromboxanes (TXs), & hydroxyl fatty acids (hydroxyeicosatetraenoic acids (HETEs).
What is the rate limiting step in eicosanoid synthesis?
Release of AA from membrane store; Requires liberation by a phospholipase
Activated by trauma, thermal injury, ischemia, endotoxin release, antigen-antibody interactions, increased intracellular calcium, cytokine production, or histamine release
PGD2
Major site: Mast cells, Langerhans Cells
Major biologic activity: neutrophil chemotaxis; induces vasodilation, relaxes smooth muscle, inhibits platelet aggregation, bronchoconstriction
PGE2
Major site: Keratinocytes, Fibroblasts & Macrophages
Major biologic activity: plasma exudation, stimulates cell proliferation, hyperalgesia, relaxes smooth muscle increases vasodilation
PGF2a
Major site: Keratinocytes
Major biologic activity: vasoconstriction, bronchoconstriction and smooth muscle contraction, stimulates cell proliferation
PGH2
Major biologic activity: precursor to thromboxanes A2 and B2, induction of platelet aggregation and vasoconstriction
PGI2
Major site: Vascular Endothelial Cells, Fibroblasts, Macrophages
Major biologic activity: inhibits platelet and leukocyte aggregation, induces vasodilation relaxes smooth muscle
TXA2
Major site: Platelets, Macrophages
Major biologic activity: induces platelet aggregation, vasoconstriction
TXB2
Major site: Platelets
Major biologic activity: induces vasoconstriction
LTB4
Major site: Monocytes, Basophils, Neutrophils, Eosinophils, Mast Cells, Keratinocytes
Major biologic activity: induces neutrophil and eos chemotaxis and aggregation/activations, vascular permeability, enhances C3B receptor expression, neutrophil degranulation
LTC4
Major site: Mast cells, Keratinocytes
Major biologic activity: Plasma exudation, mucus secretion, component of SRS-A, skin vasodilation, increases vascular permeability and bronchoconstriction
LTD4
Major site: Mast cells, Keratinocytes
Major biologic activity: component of SRS-A, skin vasodilation, mucus secretion increases vascular permeability and bronchoconstriction
LTE4
Major site: Mast Cells & Basophils
Major biologic activity:component of SRS-A, microvascular vasoconstrictor and bronchoconstriction
What are the changes in lipids from the granular to the cornified cell layers?
- Replacement of phospholipids by ceramides
- Increase in free sterols
- Large increase in free fatty acids at the expense of triglycerides and phospholipid
Transformation of these lipids provides the outer epidermal layers with a more stable, waxy, and impermeable barrier. Lipids also allow for water-holding in the stratum corneum, cohesion and desquamation of corneocytes, and control of epidermal proliferation and differentiation.
What are the two primary sources of lipids in the SC?
corneocyte envelope & intercellular lamellae
Lipids on the outer surface of the SC originate from:
Cat & Dog: predominately epidermal origin
Human: predominately sebaceous origin
What makes up the lipid portion of the CCE?
Majority are ceramides, cholesterol, fatty acids & cholesterol esters
Intercellular skin lipids are initially stored in the lamellar granules which get extruded into the extracellular space in the upper granular layer during cornification
Lamellar granules
Membrane-coating granules, Odland bodies, or keratinosomes
Secretory granules (type of lysosome) that deliver precursors of stratum corneum lipids into the intracellular space
Contain glycoproteins, glycolipids, phospholipids, free sterols, and a number of acid hydrolases, including lipases, proteases acid phosphatases, and glycosidases
Glucosylceramides are the precursors to what?
precursor to ceramides, dominant component of the stratum corneum lipids
Lipids originate in the XXX & first seen in the upper spinous layer (abundant in the granular layer)
Golgi apparatus
Complex changes in lipid composition occurs after the _______ of the granules by the enzymatic action of acid hydrolases
extrusion of the contents
Phospholipids become free fatty acids, cholesterol becomes cholesterol esters, & spingolipids become ceramides.
β glucocerebroside, acid sphingomyelinase & phospholipase A are involved in this modification
What is the intracellular lipid content?
15-25% free fatty acids
40-50% ceramides
20-25% cholesterol
5-10% cholesterol sulfate
The precursors to XXX are glucosylceramides which are located within the lamellar granules
ceramides
ceramides
the most important lipid component for lamellar arrangement in the stratum corneum & in barrier function.Plasticize the horny layer to allow stretching & bending by fluidizing barrier lipids (absence results in dissolution of water barrier)
Primary carriers of long change fatty acids and linoleic acid
Covalently linked to the corneocyte envelope
____ are incorporated into the ceramides
PUFA
Linoleic acid specifically
Free fatty acids cause an XX pH optimal for certain key enzymes
acidic
_____ and ____ are activated at an acidic pH & in turn generate ceramides
β-glucocerebrosidase and acidic sphingomyelinase (aSMase)
Acidification also regulates stratum corneum integrity/cohesion, thereby restricting desquamation
Corneodesmosomes are degraded by _____ & _____ enzymes, which exhibit optimal activity in neutral-basic pH
chymotryptic & tryptic enzymes
Lipid envelope
is located exterior to the protein envelope & is covalently attached via ester bonds to the protein envelope via TGase 1. Consists of a monomolecular layer of ω-hydroxy-ceramides which interdigitate with the intercellular lipid lamellae in a Velcro-like fashion.
Most cholesterol comes from _______ unchanged
Steroid sulfatase decreases the amount of cholesterol sulfate rather than adding cholesterol to the lipid barrier
Increases in cholesterol sulfate leads to an excess of scale (X-linked ichthyosis in humans).
Turnover rates for keratinocyte proliferation
Normal dog 22 days
Seborrheic Cocker 8 days
Horse 17 days
Goat 26 days
Pig 15 days
Human 26-42 days
16-30 from s. basale to s. spinosum
14 days in s. corneum
Desmosomes
Transmembrane Protein: Desmosomal cadherins Dsg I, II, III Dsc I, II, II
Plaque Protein: Plakoglobin, desmoplakin I, II, IV; desmocalmin; Plakophilin
Cytoskeleton Filaments: Cytokeratin
Function and Location: Cell-cell adhesion, all keratinocytes
Desmosomes
“Spines” of the spinous layer
Ca-dependent cell surface modifications that promote adhesion of epidermal cells and resistance to mechanical stress
Mechanically hold together the keratinocytes together
Physiologic communication between keratinocytes
Mediators of intercellular adhesion
Desmosomal plaque
Plakoglobin, desmoplakins I & II, keratocalmin, desmoyokin and plakophilin
Desmoplakin 1 binds directly to type ___ keratins (K1, 2, 5 & 6)
II
Keratocalmin/Desmocalmin
Calmodulin-binding protein
Promotes calcium dependent assembly and function of desmosomes
Desmogleins 1 and 3
part of the transmembrane portion of the desmosomal plaque
Calcium-dependent adhesion molecule (cadherins)
Desmocollins
part of the transmembrane portion of the desmosomal plaque
Calcium-dependent adhesion molecule (cadherins)
Cadherins
transmembrane glycoproteins
Mediate cell-cell adhesion in a Ca-dependent manner
Major adhesion molecules in desmosomes and adherens junctions
_________ is important as a mediator of adhesion
Ca
Exemplified by Darier and Hailey-Hailey disease which exhibit characteristic epidermal dyscohesion
Both are caused by mutations in genes that regulate Ca transport
Model of hemidesmosome
Keratin intermediate filaments insert into the plate portion (or inner plaque), which consists of bullous pemphigoid anitgen 230 (BP 1) and plectin.
The transmembrane component (or outer plaque) consists of bullous pemphigoid anitgen 180 (BP 2) and α6β4 integrin.
The extracellular domain of BP 180 has been localized to the extracellular space beneath the hemidesmosome (the lamina lucida) and has been identified as type XVII collagen. The intracellular domain of PB180 is localized in the hemidesmosomal plaque.
What are the extracellular components of hemidesmosomes?
Anchoring filaments originate at the hemidesmosomes and insert into the lamina densa. The major component of these filaments is laminin 5 which is localized mainly to the lamina densa and the lower lamina lucida and is associated with α6β4 in hemidesmosomes.
Plectin attaches intermediate filaments to
- HDs
- plasma membranes of basal keratinocytes
- cross-links other proteins associated with the cytplasmic plaques of HDs
Bullous pemphigoid antigen 1 (BP230, BPAG1)
First of two autoantigens in the hemidesmosones of basal keratinocytes detected using circulating autoanitbodies from patients with bullous pemphigoid (BP)
Plakin, 230 kDa; non-collagenous protein localized to the cytoplasmic plaque of HDs
Bullous pemphigoid antigen 180 (BP 2)
Type II transmembrane collagen (specifically, type XVII collagen)
Associated with HD-anchoring filament complexes in basal keratinocytes
NC16A domain of BP180
Large, non-collagenous region neat the transmembrane region
Binds extracellular N-terminus of α6-integrin
Contains the epitopes recognized by BP autoantibodies
Target of autoantibodies in a feline, porcine, and equine model of BP
α6β4 integrin
Hemidesmosome-associated integrin; receptor for Laminin 5
Large cytoplasmic tail of integrin subunit β4 contains sequences that are required for localization of in HDs
The membrane-proximal region of integrin subunit β4 directly associates with plectin, while its distal carboxyl-terminal region binds BPAG1
The proximal extracellular domain of integrin subunit α6 binds the NC16A region of BPAG2 (collagen XVII).
Laminins 1 and 5 serve as the preferred ligand for this integrin.
Mutation in either α6 or β4 integrin subunits develop Junction Epidermolysis Bullosa associated with pyloric atresia.
α5β1
mediates keratinocyte adhesion to fibronectin
α2β1
mediates keratinocyte adhesion to collagens type I and IV and laminin
α3β1
receptor for epiligrin; involved in adhesion to laminin
α1β5
mediates keratinocyte adhesion to vitronectin
α6β4
mediates keratinocytes adhesion to laminin
β2 integrins
Leukocyte functional antigen-1 (CD11a/CD18)
Adhesion molecule on T lymphocytes
Essential for most adhesion-dependent lymphocyte function
MAC-1, CR3, CD11b/CD18 and CD11c/CD18 (CR4)
Found on mononuclear phagocytes, neutrophils, NK cells
Adherens junctions
Small punctuate cell-cell attachment points
Connect actin filaments to adjacent cells
Major players: E and P cadherins
E-cadherins
Associated with actin filaments via interactions with catenins, and may regulate the orgainziaiton of adherens junctions and influence epidermal stratification
Expressed in keratinocytes of all epidermal layers
P-cadherins
expressed only in basal keratinocytes
Cytoplasmic domains of the cadherins connects with α- and β-catenin, and plakoglobin (γ-catenin).
Catenins connect cadherins to the cytoskeletal network of β-catenin & plakoglobin; α-catenin directly associates with acitn
Tight Junctions
An intercellular junction composed of a series of fusions of the junctional membrane, forming a continuous seal
Serves as a selective barrier to small molecules and as a total barrier to large molecules
Also known as impermeable junction; occluding junction; zonula occludens
Most important tight junction proteins in the human epidermis:
Occludin, claudins, and zonal occluding proteins
Occludin: restricted to the stratum granulosum
Zonal occluding protein-1 & claudin-4: found in the suprabasal layers
Claudins-1 & -7: found in all epidermal layers
Gap junctions
Sites of physiologic communication; while desmosomes/hemidesmosomes are sites of mechanical coupling
More abundant in more differentiated keratinocytes
Consist of 2 connexons from adjacent cell membranes
Connexins
Intracellular gatekeepers
Transmembrane proteins
Connexons on adjoining cells associate to form gap junctions
Different connexin based on layer of epidermis
Basal: Connexin 43
Spinous: Connexin 26
Cornified cells: Connexons 31 and 31.1
These changes relate to intracellular ionic signaling (specifically calcium)
Connexin-26 is one of the most highly upregulated genes in human psoriatic plaques
Missense mutations of connexin-26 result in 5 distinct ichthyosis-like skin disorders
Skin-associated lymphoid tissue
Langerhans’ cells, keratinocytes, epidermotrophic T lymphocytes, & draining peripheral lymph nodes
List 5 immunologic role of keratinocytes
Produce IL-1
Produce various cytokines (IL-3, protaglandins, leukotrienes, interferon)
Are phagocytic
Can express antigens associated with immune response gene in a variety of lymphocyte-mediated skin diseases (presumably as a result of interferon-γ secretion by activated lymphocytes)
Immunologic activity of unperturbed skin
produce only a few mediators
Cytokines: IL-1, IL-7 & transforming growth factor-β (TGF-β)
Contain large quantities of pre-formed & biologically active IL-1α and immature IL-1β
immediate initiator of inflammatory and repair processes after epidermal injury
IL-7
important lymphocyte growth factor
TGF-β
growth-regulating effects on keratinocytes
Modulates inflammatory/immune response
Important for Langerhans’ cell development
Antimicrobial peptides
an important evolutionary conserved innate host defense mechanism in many organisms
Keratinocytes produce cathelicidins (IL-37) and β-defensins
MOA may relate to membrane insertion and pore formation
β-defensins
Cysteine-rich cationic low-molecular-weight antimicrobial peptides
Essential part of cutaneous innate immunity
Attract dendritic cells and memory T cells via CC cehmokine receptor 6 (CCR6)
Cathelicidins:
cationic peptides with a structurally variable antimicrobial domain at the C-terminus
In mammals, pigs & cattle – a variety of cathelicidin genes exists
Pronounced antibacterial, antifungal, and antiviral activities
Attracts mast cells and neutrophils
Secreted into human sweat
Down regulated in atopic dermatitis
Psoriasin (S100A7)
secreted predominately by keratinocytes
plays a major role in killing E. coli
Keratinocytes synthesize and release complement components ___ and factor ___.
C3 and factor B
Eicosanoids
an ensemble of lipid mediators regulating inflammatory and immunologic reactions
Can produce and release the cylcooxygenase product prostaglandin E2, (both pro-inflammatory and immunosuppressive proteins)
When acting on dendritic cells, promotes the development of IL-4 dominated type 2 T cell responses
Things that stimulate keratinocyte growth
1) EGF
2) Transforming growth factor α
3) KGF
4) IL-1 α
5) IL-6 (increasing UV light)
6) β-FGF
Difference between neoplastic and regular keratinocytes
1) Neoplastic cell cycle shorter
2) Neoplastic cells have whorls
3) Anisocytosis
4) Lacks cells surface antigens
5) Growth faster without Cholera toxin and EGF
Integrins
Large family of cell surface adhesive receptors (surface glycoproteins)
Important in cell-cell and cell-matrix interactions
Facilitate association of matrix molecules and basal keratinocytes
Act as a link for collagen, laminin, fibronectin, thrombospondin, and vitronectin to the cytoskeleton of keratinocytes
Vital for communication
β1 integrins
found on the lateral surfaces of keratinocytes
Downregulated during differentiation, thought to be important for extracellular matrix attachment
β4 integrins
found associated with hemidesmosomes; mediates station adhesion
During wound healing, ____ integrins are redistributed to promote keratinocyte migration on matrix molecules like fibronectin.
B1 integrins
Integrins α5β1 and ανβ1 are also involved with wound healing
Difference between Epidermal growth factor (EGF) and TGF
EGF is not produced by keratinocytes; TGF is produced by keratinocytes
Both bind to the same tyrosine kinase receptor in the basal cell and suprabasal cell layers to stimulate proliferation
Over-expression leads to hyperplasia, hyperkeratosis, formation of spontaneous papillomas and hyper proliferative disorders
Keratinocyte-derived growth factor (KGF)
dermal transcripts with receptors on keratinocytes
member of the fibroblast growth factor family
Potent mitogen for keratinocytes
Ectopic expression will lead to epidermal thickening
Transforming growth factor β (TGF-β)
causes a decrease in DNA synthesis and mitosis of keratinocytes, promotes differentiation
TGF-β1 and TGF-β2 are expressed in the upper epidermal layers;
upregulated by TGF-β as well as other agents that promote differentiation (ie Ca)
Important role in homeostatic regulation of the epidermis
Other growth factors produced by keratinocytes include Basic fibroblast growth factor (influence on the proliferation of melanocytes) & platelet-derived growth factor (functions in the dermis)
Vitamin D3 effects on proliferation and differentiation?
Causes a decrease in keratinocyte proliferation
Causes an increase in keratinocyte differentiation
Terminal Epidermal Differentiation Processes that are Calcium-Dependent
Intercellular structure formation – Desmosome assembly & function, Gap junction assembly & function
Protein Expression – Involucrin, Keratins 1, 2e, 9, & 10, Loricrin, Profilaggrin, Small proline-rich peptides, Transglutaminase
Release of keratohyaline granule contents – Release of loricrin & profilaggrin
Enzyme function – Cleave of profilaggrin to filaggrin, Transglutaminase activity
Optimal water concentration of SC
20-35%
Must be at least 10% to look & feel normal
Atopy and filaggrin defect in humans
Atopic dermatitis (eczema) in humans affects ~20% population Two independent loss-of-function genetic variants in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis
Origin of melanocytes?
Neural Crest
Location of melanocytes?
Basal layer of the epidermis
outer root sheath and hair matrix of hair follicles
ducts of sebaceous and sweat glands
perivascularly in the superficial dermis
Eye, ear, and CNS
There are no histochemical stains the cane performed on routinely process skin biopsy specimens that exclusively stain melanin. What stains rely oj the ability o melanin to reduce silver from a silver solution.
Do not stain readily with hematoxylin eosin and actually show up clear
Argentaffin stains rely on the ability of melanin to reduce silver from a silver solution. Examples of argentaffin stains include Fontana Masson and GMS. Argyrophil are similar stains but use an external suaver reducer to produce elemental silver (Grimelous stain).
These agents also stain neurosecretory granules and formalin pigment.
IHC of Melanocytes?
Positive for vimentin and S-100 protein
Melanocytes produce what cytokines in response to inflammation?
Secrete IL-8, IL-1α, TNFα, MCF in response to inflammation
Functions of melanocytes:
cosmetic entity: protective coloration (camouflage and mimicry), social communication (sexual attraction)
barrier against ionizing radiation: protection against UV light
scavenger of cytotoxic radicals and intermediates: esp. during rapid proliferation and differentiation of the hair follicle
additional roles include: restrain keratinocyte proliferation, calcium homeostasis
secrete IL-8, IL-1α, TNFα, MCF in response to inflammation
Pigmentation: Steps (4 steps)
The synthesis and distribution of melanin in the epidermis, involves several steps:
Transcription of proteins required for melanogenesis
Melanosome biogenesis
Transport of melanosomes to the tips of melanocyte dendrites
Transfer of melanosomes to keratinocytes
Constitutive pigment
the pigmentation that is genetically determined in the absence of stimulatory influences
Facultative pigment
the pigmentation which occurs with various stimuli (ex UV light, inflammation, hormones)
Normal human skin colors and pigments (4)
Red: Dermis by oxygenated hemoglobin
Yellow: Epidermis by exogenously produced carontenoids
Brown: Endogenously produced melanin
Blue: Dermis by unoxygenated hemoglobin in venules
What is the rate limiting step in melanogenesis?
Tyrosinase is the rate limiting enzyme in the melanin pathway
Melanogensis place exclusively within melanocytes and on the specialized organelle, the melanosome
Where are the majority of melanocytes present?
Largest number of melanocytes is present in the skin and hair
Present in the epidermal basal layer
Approx 1 melanocyte per 10-20 basal keratinocytes in dogs
Nevi and melanomas
mislocation of melanocytes in the dermis.
Constant need for synthesis and transfer of melanosomes from melanocytes to keratinocytes to maintain continuous pigmentation
Where is the only site of pigment production for the hair shaft? How are these different that epidermal melanocytes?
Hair bulb: only site of pigment production for the hair shaft
Located in the proximal hair bulb during anagen phase
Differ from epidermal melanocytes by being larger, more dendritic, with more extensive Golgi and RER, and by producing larger melanosomes.
Melanocytes proliferate, migrate, & undergo maturation during _____
early to mid-anlagen
Depends on c-Kit expression by melanocytes and SF synthesis by keratinocytes
Melanogenesis & melanin transfer to keratinocytes occur throughout anagen phase
Melanocytes apoptose during late catagen
Melanogenically active melanocytes are restricted to the upper hair matrix of the anagen hair follicle, below the pre-cortical keratinocyte population, correlating with the anagen transfer of melanin predominately to the hair shaft cortex, less to the medulla, & only rarely to the hair cuticle
Melanocytes determine hair color by the amount of ______ transferred as well as by the ____ of eumelanin (black-brown) to pheomelanin (red-yellow)
melanin
ratio
Define Graying
the gradual decline in the melanogenically active melanocytes in the hair bulb (determined by age and genetics); there is also a component of ineffective melanosome transfer
Where do ocular melanocytes reside? What is their main function?
Reside in the cochlea; important for hearing
Reside as intermediate cells of the stria vascularis
A loss of otic melanocytes leads to deafness.
Help in the maintenance of the endolymph through the regulation of potassium transport
Endolymphatic fluid of the cochlea maintain high concentrations of positively charged ______.
high concentrations of positively charged potassium
In the absence of cochlear melanocytes, the endolymphatic potential is low, leading to deafness.
Congenital Hereditary Sensorineural Deafness - what are the genes involved in cats and dogs?
Usually seen in dog and cat breeds with white pigmentation
Dogs carrying the piebald or merle genes & cats carrying the white gene, the hair cell loss is secondary to degeneration of the cochlear blood supply
studies demonstrate an absence of strial melanocytes
In the Dalmatian, postnatal auditory function development has been shown to proceed normally up until 3 wks at which point the strial degeneration produces rapid loss of hair cell function
In general, loss of melanocytes at any age — deafness
Waardenburg syndrome type 2
deaf due to lack of melanocytes within the inner ear (like the Dalmatian)
***However there is a preservation of hearing in albinos, which indicates that melanin production within otherwise viable melanocytes are not essential for hearing. BUT albinos are more susceptible than the normal population to hearing loss from noise and/or exposure to toxic agents, therefore melanin provides some protective effect.
Where are cephalic melanocytes located?
Dispersed throughout the meninges; particularly dense in the leptomeninges above the pons and medulla oblongata.
Function as scavengers for toxic cations and ROS
Melanocytogenesis
- Precursor cell (melanoblasts) development and migration from the neural crest to peripheral sites
- Differentiation of melanoblasts into melanocytes
- Survival and proliferation of melanocytes
- Synthesis of melanosomes and melanin
