2018 Group Project 3

From Embryology
Projects 2018: 1 Adrenal Medulla | 3 Melanocytes | 4 Cardiac | 5 Dorsal Root Ganglion

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Melanocytes

Introduction

Diagram of an epidermal melanocyte and its structures

Melanocytes are a type of neural crest-derived cells in the body [1], most commonly found in the stratum basale, the bottom layer of the epidermis of the skin, eyes [2], and to a lesser known degree, the meninges (membrane around the brain), the heart [3] and the inner ear [4].

Each melanocyte possesses a main cell body, where most of the cellular functions, including the production of melanin take place. They also possess finger-like projections that extend into the surrounding tissue, similar to neurons, called dendrites.

Their most commonly known function is the production of melanin, melanogenesis, of which there are two types; eumelanin (black) and pheomelanin (reddish yellow) [5], and are responsible for the pigmentation of various parts of the human body including the skin, hair and irises, etc. Melanogenesis has different levels, basal and activated. The basal level of melanogenesis determines an individual's skin colour and is determined by genetics, i.e. a light-skinned individual has low levels of basal melanogenesis. Activated levels of melanogenesis are usually due to external factors, such as exposure to UV-B radiation, resulting in increased levels of melanogenesis [6], which can be commonly seen as sunburn or tan after long exposure to sunlight.

Melanin produced with the cell is packaged into granules, before being transported to the surrounding cells via dendrites which reach in between the surrounding tissue.

History

Melanocytes were first described and named ‘chromatophores’ by Giosué Sangiovanni in 1819, who identified them in squid [7] . The location of pigmentation in the skin was examined by various scientists from the 1600s, and found to be located specifically in the epidermis. But it wasn't until the early 20th century that the dark granules responsible for this pigmentation, nowadays termed melanosomes, were first identified using of light microscopy. The origin of melanosome synthesis within the cell was discovered later in the century using electron microscopy: in 1961, Moyer found that stage 1 melanosomes (those containing matrix material, but no melanin), in pigmented retina, originate from the endoplasmic reticulum of epithelial cells. These findings were later confirmed by Turner, who studied melanosomes in goldfish [8] [9].

The idea that melanocytes originate from neural crest cells was first suggested by Ross Granville Harrison in 1910, when writing a paper on the outgrowth of the nerve fibre [10]. This was later proven by DuShane in 1935: He removed sections of neural fold in stage 15 Amphibia punctatum and tigrinum embryos, and observed a lack of pigment in their trunk region. He then placed the neural fold tissue explants in Holtfreter’s solution (a solution designed to facilitate amphibian development), and observed their differentiation into melanocytes [11]. In an article published in 1963, James Weston describes using tritiated thymidine labelling to track chick embryo neural crest migration in vivo. He identified a dorsolateral stream of neural crest derived melanoblasts (precursors to melanocytes), migrating to enter the ectoderm [12].

Tissue Organ Structure and Function

Skin

Skin melanocytes are located in the basal layer of the skin epidermis. These melanocytes produce melanosomes - granules containing the pigment melanin [13]. Melanocytes synthesise two types of melanin: pheomelanin, which is red/yellow; and eumelanin, which is brown/black. These are produced in varying proportions depending on the individual. Paler skinned individuals synthesise more pheomelanin, whilst darker skinned individuals synthesise more eumelanin [5].

We all have around the same number of melanocytes in our skin epidermis, but the quantity of melanosomes taken up into keratinocytes varies between individuals - this is what causes variation in skin colour. The darkening of skin can occur due to two causes: Ultraviolet irradiation and locally produced α-Melanocyte-stimulating hormone (α-MSH), both of which stimulate melanogenesis [14][15][5].

Mature melanosomes travel from the cell body to the dendrites of the melanocyte, where they are transported to neighbouring keratinocytes. A recent study has shown that melanocyte dendrites release pigment globules that contain clusters of melanosomes into the extracellular space. The pigment globules are then phagocytosed by keratinocytes. The globule membrane degrades in the keratinocyte cytosol and the melanosomes are released to populate the perinuclear space [16].

In the skin, melanin has a protective role, as it acts as a barrier to DNA damage in the nuclei of keratinocytes - it absorbs ultraviolet radiation, thus providing photoprotection [17].

Ears

Figure 2: Diagram of the Stria Vascularis, containing the marginal cells, intermediate melanocytes and basal cells. It shows marginal cell extensions intercalating with melanocytes, and the K+ ion channels involved in generating the EP [18].


Melanocytes are mainly present in the cochlea, vestibular organ and endolymphatic sac:


The cochlea of the inner ear functions as a transducer, by converting sound vibrations to electrical potentials in the auditory nerve via hair cells [19]. In the cochlea of humans, melanocytes are found in the vascularised epithelial tissue in the intermediate layer of the stria vascularis and the modiolus, between the marginal and basal cell layers [20](Figure 1). During development, marginal layer cuboidal epithelium develops processes which interdigitate with the intermediate melanocytes and basal cells [21].Based on studies performed on mice models, it is thought that melanocytes are important for the development of the endocochlear potential (EP), produced by strial cells. Intermediate melanocytes conduct K+, which plays an important role in sound conductance, as it flows from the endolymph into the ciliated epithelial cells of the ear via mechano-electrical channels. This influx of K+ is driven by a combination of the membrane potential of these ciliated epithelial cells, and the EP. A study on guinea pig models showed that blocking the K+ channels of melanocytes produces a lower EP [22]. This study agrees with evidence showing that mice deficient in cochlea melanocytes have a lower EP, requiring a greater sound stimulus to produce an action potential [23].

Figure 3: The cochlea of a Wv/Wv viable dominant spotting mutant - a mutation in both alleles encoding c-kit, an essential growth factor for formation, migration, proliferation and differentiation of melanoblasts. The distribution of melanocytes are shown as dots within the Stria Vascularis of the left cochlea [23].

Eyes

Uveal melanocytes contain both eumelanin and pheomelanin. It has been speculated that eumelanin is photoreceptive, whereas pheomelanin is phototoxic. Uveal melanocytes produce growth factors, such as vascular endothelial growth factor that controls blood circulation around the eye, as well as extracellular matrix degrading enzymes. It was found that both of these roles may play a key part in the toxicity of uveal melanocytes. [24]The uveal tract (iris, ciliary body and choroid) and conjunctiva normally contains melanocytes derived from the neuro-ectodermal neural crest. Peri-orbital soft tissue is also derived from the embryonic neural crest.[25] On the other hand, pigmented melanocytes (such as those found on the retina) were derived from the neuroepithelium or from different layers of the optic cup. [26] Uveal melanocytes (like all other melanocytes) differentiate into melanin-producing cells, which in this case determines a person's eye colour, protects the eye from UV radiation [27] and can mutate to form many ocular diseases that can cause blindness, including age-related macular degeneration. [28] Melanocytes found in the eye are not able to participate in regeneration unlike epidermal melanocytes. [29]

Figure 4. Pigmentation of the anterior segment of the eyes in B6 and ep mice. (A) Sagittal diagram of anterior eye of adult mouse. Tissues containing melanocytes derived from the neural crest were italicised and pigmented cells derived from the neuroepithelium of the optic cup were underlined. (B) Pigmentation of the anterior segment of the eyes of B6 and ep mice. As shown in the upper-left photo, the iris is defined as the part of tunica vascularis beneath the dotted line; ciliary body is defined as the part between solid and dotted lines; choroid/retina is defined as the part above the solid line. The bar indicates 100 mm. (C) Pigmentation of the ciliary body and ciliary storm in postnatal days, adult, and 3 months old. The bar indicates 50 mm.

Heart

The term ‘cardiac melanocytes’ is used to describe the population of cells found in the human heart that express the melanin-synthesis enzymes. These cardiac melanocytes also resemble the morphology of the melanocytes found at the cutaneous level [30].

Figure 5. A differential interference contrast (DIC) microscopical image of a cardiac melanocyte present in an isolated atrial cell of an embryonic mouse pup. The white arrow indicates the cardiac melanocyte that is found amidst the atrial myocytes that are marked by the yellow arrowheads. [30]

Central Nervous System

A diagram displaying the layers in the skull, including the meninges.

Melanocytes can also be found within the Central Nervous System, primarily in the leptomeninges [31], which consists of the inner two layers membranes of the meninges, the pia mater and arachnoid, which encapsulate the brain and the spinal cord. While its function within the meninges is unknown, they are essential to the health of the meninges, with their removal increases the risk of aseptic meningitis [32]. Furthermore, due to its receptivity to the same signalling molecules as neurons, scientists can study diseases afflicting the central nervous system using it as a model [33].

Embryonic Origins

As mentioned earlier, melanocytes originate from the pluripotent cells in the neural crest [1]. After formation of the neural tube, neural crest cells eventually form four different functional domains, namely the cranial neural crest, trunk neural crest, vagal and sacral neural crest, and the cardiac neural crest [34]. Melanocytes are descended from melanoblasts, which in turn are formed from trunk neural crest cells migrating along the dorsolateral pathway into the ectoderm via minute holes in the basal lamina [35]. These eventually form part of the ears, eyes, skin and leptomeninges, therefore explaining the presence of melanin in these parts as a result of the development of melanoblast subpopulations during early migration [36].

Cochlear melanocytes of the inner ear

These melanocytes have recently been found to originate from neural crest cells delaminating from the rhombomere 6 region of the hindbrain, where the glossopharyngeal nerve and third pharyngeal arch are located [18].

Development Time Course

Melanocytes originate from neural crest cells, where they migrate to and localise in many different parts of the embryo during the first trimester of embryogenesis (in particular between weeks 4 to 18). Skin melanocytes follow hair follicles closely and localise around them, but little is known about melanocytes in volar skin (skin of the palms and soles), but it is suggested that they localise around eccrine sweat glands. [37]

Week 4= Visible neural plate where neural crest cells derive from.

Weeks 6-8= Melanoblast (pre-cursor cell of melanocytes) migration along dorsolateral trunk. Melanoblast proliferation also takes place along pathway, as the cells reach their areas of localisation, such as the eyes and the meninges. Melanoblasts have to migrate over incredibly long distances within the embryo, while at the same time proliferating and maintaining their chances of survival, so their development is a very dynamic process.

Weeks 9-12= Beginning of melanoblast migration to developing hair buds.

Weeks 12-13= A majority of melanoblasts are located in the epidermis and hair follicles. All melanoblasts differentiate into melanocytes.

Week 18= Hair breaks through skin surface containing melanocytes. [38]

Molecular Mechanisms/ Factors/ Genes

    • unedited **

melanocytes in the skin-

transcription factors* microphthalmia-associated transcription factor (MITF)

intrinsic factors: - Hmx1 - Krox20

extrinsic factors modulating Hmx1 and Krox20: - Neuregulin-1 - IGF - PDGF

derivation pathways: - differentiate from ncc via dorsolateral path - from schwann cell precursors via ventral pathway

[29].

Animal Models

Zebrafish Melanoma Model Reveals Emergence of Neural Crest Identify During Melanoma Iniitation

Figure 7. Neural crest reporter expression in melanoma.

Genetically Engineered Mice (GEM) Models For Melanocyte Development

The development of melanocytes in mice and humans are very similar, except they take longer to form in humans, so mice can be used to study melanocytes as they would occur in the human body. SCF (melanocyte growth factor) is essential for the maintenance and survival of melanocytes throughout life. The receptor for SCF is c-kit, and if it mutates, it can lead to sterility, anaemia and pigmentation disorders. If the receptor is completely lost, it results in loss of melanocytes, primordial germ cells and haematopoietic stem cells completely. In embryonic development however, ETRB (endothelin receptor) is more important to melanocyte developed compared to c-kit, as it regulates the number of precursor melanoblasts that will differentiate into melanocytes. [39]

Figure 8. Overall scheme for the generation of genetically engineered mice.

Genetically Engineered Mice (GEM) Models For UV-induced Melanoma

UV-induced melanoma is explored in GEM as the skin of a mouse is similar to the skin of a human except that mice are covered in hair that undergo frequent cycles for follicular development, which in turn causes mature melanocytes to be shed. There is also a distinct difference in the levels of eumelanin and pheomalanin between mice and humans. These mice models allowed scientists to study the part UVR plays in melanomagenesis, in particular those that over-expresses HGF (hepatocyte growth factor). [40]

Current Research

Generation of Melanocytes from Induced Pluripotent Stem Cells (iPSCs)

Melanocytes can be derived from autologous iPSCs, meaning the cells come from the one person. In this case the likelihood of the melanocytes being rejected by the immune system of the person they are being implanted in, is incredibly low. A benefit of autologous iPSCs from a patient with a pigmented disorder (such as albinism), is that the pathogenesis can be studied in order to find a suitable treatment for the disease, and possibly a cure. [41]

Altered Chromosome Expression of Uveal Melanoma in the Setting of Melanocytosis

Uveal melanoma seems to effect chromosomes 3p, 3q, 1p, 8p and 8q in particular as they show the most significant areas of DNA loss or amplification. However, the most important DNA alteration is monosomy on chromosome 3. In melanocytosis tissue, there is normalcy on chromosome 1, 3, 6 and 8, but there is exhibited disomy on chromosome 3. Ocular melanocytosis is predicted to impart a 1/400 lifetime risk of uveal melanoma in Caucasian individuals (which is 400x higher than the general population). It has been found that alterations in chromosome 3 does not always lead to the development of uveal melanoma, but it does take place sometime during the tumour development. [42]

Abnormalities

Skin

Abnormalities associated with melaoncytes are often caused by disruptions to or loss of function of the pigmentation and its related factors. These pigmentary disorders are classified as hyperpigmentation disorder, hypopigmentation disorder, mixed hyperpigmentation disorder and mixed hypopigmentation disorder which are further subclassified into acquired and congenital [29].

Ears

Waardenburg Syndrome

There are varying forms of Waardenburg Syndrome, but they all result in deafness due to loss of melanocytes in the inner ears. As explained in the above section "Tissue Organ Structure and Function", melanocytes are necessary for sound transduction. The mutations that cause Waardenburg Syndrome, result in a lack of Melanogenesis Associated Transcription Factor (MITF) expression. MITF is a protein which works along side the transcription factor LEF-1 to regulate melanocyte gene expression [43]. These mutations may be in Sox10 and Pax3 genes, as these both regulate the expression of the MITF protein [44][45]. Hence, Waardenburg Syndrome can have varying genetic causes, but with the same outcome.

Sensorineural hearing loss (SNHL)

Eyes

Uveal Melanoma

Melanoma that occurs in the eye is known as uveal melanoma. This is an uncommon form of cancer that only accounts for about 3% of all melanomas. The risk factors of this cancer are light skin colour, red or blonde hair and blue or light irises. [25]. About 95% of uveal melanomas occur in the posterior eye (the ciliary body and choroid). Even though this is a rare from of cancer, it still contributes to a large percent of deaths and has a high chance of leading to distant metastases despite successful initial therapies in the local tumour or tumours of the eye. [46]

Heart

Central Nervous System

Glossary

Autologous- cells or tissues obtained from the same individual

Melanoblasts- melanocyte pre-cursor cells

Melanocytosis- the presence of an excessive number of melanocytes

Melanoma- a tumour of melanin-forming cells

Volar Skin- skin of the palms of the hands and the soled of the feet (thick skin)

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