20: Pigmentation and Melanocyte Biology Flashcards
(133 cards)
1
Q
What is the primary function of melanocytes in the skin?
A
Melanocytes synthesize melanin and transfer it to adjacent keratinocytes, playing a crucial role in pigmentation.
2
Q
How do the melanin granules differ between light-skinned and darker-skinned individuals?
A
Light-skinned individuals have very few visible melanin granules in the basal layer, while darker skin types have melanin granules visible throughout all layers of the epidermis, including the stratum corneum.
3
Q
What are the key structural features of melanosomes in melanocytes?
A
Melanosomes are round to oval-shaped membrane-enveloped organelles that are key ultrastructural features of melanocytes, involved in melanin synthesis and storage.
4
Q
What are the stages of eumelanosome and pheomelanosome development?
A
The stages of eumelanosome development include:
- Round, ~0.3 μm, containing intraluminal vesicles (not melanized)
- Oval, ~0.5 μm, with deposition of parallel fibrillar matrix
- Deposition of pigment along the filaments
- Fully melanized with electron-dense melanin obscuring underlying structures
Pheomelanosomes are smaller, round at all stages, disorganized, and have a less dense filament network.
5
Q
What transcription factors are important for the development and function of melanocytes?
A
Key transcription factors for melanocyte development and function include MITF, SOX10, PAX3, and signaling pathways involving KIT and EDNRB.
6
Q
What is the significance of tyrosinase in melanocytes?
A
Tyrosinase is an enzyme that catalyzes the oxidation of the substrate dopa to insoluble black melanin, reflecting its activity in melanosomes and is crucial for melanin synthesis.
7
Q
What are the clinical features associated with Ocular albinism (OA1)?
A
- Reduced pigmentation of iris and retina
- Photosensitivity
- Decreased visual acuity
- Nystagmus
- Strabismus
- Misdirection of optic nerve
8
Q
What genetic mutations are associated with Waardenburg Syndrome and what are its clinical features?
A
Genetic Mutations:
- WS1: PAX3
- WS2: MITF
- WS3: PAX3
- WS4: SOX10, EDN3, EDNRB
Clinical Features:
- Piebaldism
- Congenital deafness
- Heterochromia irides
- Synophrys
- Broad nasal root
- Dystopia canthorum
9
Q
What are the clinical features of Hermansky-Pudlak syndrome (HPS)?
A
- Tyrosinase-positive oculocutaneous albinism (melanosome dysfunction)
- Bleeding diathesis (platelet granule dysfunction)
- Interstitial pulmonary fibrosis (HPS 1,2,4)
- Granulomatous colitis (HPS 1,4)
- Renal failure (rare)
- Cardiomyopathy (rare)
10
Q
What are the characteristics of Familial progressive hyperpigmentation (FPH)?
A
- Generalized patches of hyperpigmentation of skin and mucous membranes
- No systemic symptoms
11
Q
What are the clinical features of Griscelli Syndrome?
A
- Pigmentary dilution of skin and hair (clumping of melanin within melanocytes)
- Neurologic abnormalities (GS1)
- Immunodeficiency (GS2)
12
Q
What are the key clinical features of Hermansky-Pudlak syndrome (HPS) and its genetic basis?
A
Hermansky-Pudlak syndrome (HPS) is characterized by tyrosinase-positive oculocutaneous albinism, bleeding diathesis (platelet granule dysfunction), interstitial pulmonary fibrosis, and immunodeficiency. It is linked to mutations in various genes including HPS1 and HPS3.
13
Q
What distinguishes Familial progressive hyperpigmentation (FPH) from Familial progressive hyper- and hypopigmentation (FPHP) in terms of clinical features?
A
Familial progressive hyperpigmentation (FPH) is characterized by generalized patches of hyperpigmentation of skin and mucous membranes without systemic symptoms, while Familial progressive hyper- and hypopigmentation (FPHP) presents with diffuse hyperpigmented and hypopigmented patches without systemic symptoms, showing variable penetrance.
14
Q
What is the distribution of interfollicular melanocytes in human skin and how does it vary by location?
A
Interfollicular melanocytes are found in the basal layer of the epidermis, with the highest density in facial and genital skin, and lower density in the skin of the trunk and extremities. Chronic, sun-exposed skin has a 2-fold higher number of melanocytes and increased size and activity.
15
Q
What is the role of melanocyte stem cells (McSCs) in the hair follicle cycle?
A
Melanocyte stem cells (McSCs) reside in the permanent bulge area of the hair follicle. They maintain a quiescent state during telogen, become activated during anagen, migrate to the hair bulb, and differentiate to produce melanin, which is transferred to keratinocytes, resulting in hair pigmentation.
16
Q
How do acral melanocytes differ from other melanocytes in terms of location and clinical significance?
A
Acral melanocytes are located in the hairless surfaces of palms and soles. They are derived from the lower permanent portion of the eccrine gland and are associated with acral melanoma, which is diagnosed with high sensitivity and specificity due to their preferential pigmentation of eccrine-rich dermatoglyphs.
17
Q
What are the implications of ocular melanocytes in relation to UV protection and age-related conditions?
A
Ocular melanocytes, derived from neuroectoderm, synthesize melanin to protect against UV radiation. Darker eye pigmentation is associated with a decreased incidence of age-related macular degeneration, highlighting their protective role.
18
Q
What is the significance of melanocytes in the cochlea of the ear?
A
Melanocytes in the cochlea are essential for the normal development and function of the stria vascularis layer, which is required for normal hearing. Defects in this layer can lead to sensorineural deafness and pigmentation defects in conditions like Waardenburg and Tietz syndromes.
19
Q
What is the primary determinant of skin pigmentation in humans?
A
The primary determinant of skin pigmentation is not melanocyte density but the increased ability of melanocytes from darker-skinned persons to synthesize and transfer brown-black eumelanin.
20
Q
Describe the role of melanocyte stem cells (McSCs) during the hair follicle cycle and their significance in hair pigmentation.
A
Melanocyte stem cells (McSCs) reside in the permanent bulge/secondary hair germ (sHG) area of the hair follicle. Their roles include:
- During telogen: Maintain a quiescent state.
- During anagen: Become activated via Wnt signaling, proliferate, and differentiate into melanocytes.
- Early to mid-anagen: Migrate to the bulb of the hair follicle and undergo maturation.
- Throughout anagen: Produce and transfer melanin to surrounding keratinocytes, resulting in hair pigmentation.
- Late catagen: Undergo apoptosis, leading to a gradual loss of McSCs with age, contributing to age-dependent hair graying.
21
Q
What is the significance of acral melanocytes in the context of acral melanoma, and how are they diagnosed?
A
Acral melanocytes exist in the hairless surfaces of palms and soles, and they are significant because:
- They provide a niche for melanocyte stem cells (McSCs) in the acral epidermis.
- Acral melanoma is derived from this McSC population.
- Diagnosis of acral melanomas is characterized by high sensitivity and specificity due to their preferential pigmentation of the eccrine-rich ridges of the dermatoglyphs.
22
Q
Explain the role of ocular melanocytes and their developmental origin.
A
Ocular melanocytes, specifically those in the retinal pigment epithelium, synthesize melanin and form melanosomes. They are derived from neuroectoderm and are developmentally unrelated to the neural crest/melanocyte lineage. Their primary role is to protect against UV radiation.
23
Q
What is the role of MITF in melanocyte development and migration?
A
MITF is crucial for the survival, proliferation, and differentiation of melanocytes. It is first expressed in melanoblasts shortly after they exit the neural tube and is positively regulated by transcription factors like SOX10 and PAX3.
24
Q
How do mutations in SOX10 and PAX3 affect melanocyte function?
A
Mutations in SOX10 and PAX3 lead to pigment cell defects and non-pigmentary phenotypes. Specifically, SOX10 mutations are associated with Waardenburg syndrome type IV, while PAX3 mutations are linked to Waardenburg syndrome types 1 and 3.
25
What are the embryonic stages of melanocyte migration from the neural crest?
The stages of melanocyte migration from the neural crest include:
1. **E10.5 - 11**: MITF is first expressed in melanoblasts after exiting the neural tube.
2. **E11.5**: Melanoblasts move to the migration staging area (MSA).
3. **E12.5**: Melanoblasts travel along the dorsolateral pathway and express melanogenic enzymes Dct and TYRP1.
4. **E12.5 - 13.5**: Melanoblasts enter the epidermis in a synchronous wave.
5. **E14.5**: Melanocytes express tyrosinase.
6. **E15.5**: Clusters of epidermal melanoblasts migrate and populate hair follicles.
7. **E16.5**: Melanocytes display pigmentation.
26
What is the significance of the migration staging area (MSA) in melanocyte development?
The **migration staging area (MSA)** is critical as it is where melanoblast precursors stall after exiting the neural tube. From the MSA, they move between the somites and the ectoderm to migrate along the dorsolateral pathway.
27
A patient with Waardenburg syndrome type 2a presents with hearing loss and pigmentation defects. Which gene mutation is most likely responsible?
The mutation is in the MITF gene. MITF is critical for melanocyte survival, proliferation, and differentiation.
28
A patient with Waardenburg syndrome type IV has megacolon and pigmentation defects. Which gene mutation is implicated?
The mutation is in the SOX10 gene. SOX10 is required for the development and survival of melanocyte neural crest lineages.
29
A patient with sensorineural deafness and pigmentation defects is diagnosed with Waardenburg syndrome. Which transcription factor is most likely mutated?
The transcription factor PAX3 is most likely mutated. PAX3 is critical for neural crest development and melanoblast proliferation.
30
A patient with Waardenburg syndrome type 1 has hearing loss and pigmentation defects. Which gene mutation is implicated?
The mutation is in the PAX3 gene. PAX3 is critical for neural crest development and melanoblast proliferation.
31
A patient with a mutation in the MITF gene shows pigmentation defects. How does MITF regulate melanogenesis?
MITF regulates melanogenesis by controlling the expression of tyrosinase and other melanogenic enzymes. It is essential for melanocyte survival and differentiation.
32
A patient with a mutation in the SOX10 gene shows complete absence of melanoblasts. What is the role of SOX10 in melanocyte biology?
SOX10 is required for the development and survival of melanocyte neural crest lineages.
33
What is the role of MITF in melanocyte differentiation and migration from the neural crest?
MITF is crucial for the **survival**, **proliferation**, and **differentiation** of melanocytes. It is first expressed in melanoblasts shortly after they exit the neural tube.
34
How do mutations in PAX3 affect melanocyte development?
Mutations in PAX3 are linked to **Waardenburg syndrome types 1 and 3**, which can cause **hearing loss**, **pigmentation defects**, and **developmental defects** in the arms and hands.
35
What are the effects of mutations in MITF?
Mutations in MITF can lead to pigmentation defects and are associated with Waardenburg syndrome.
36
How do mutations in PAX3 affect melanocyte development?
Mutations in PAX3 are linked to Waardenburg syndrome types 1 and 3, which can cause hearing loss, pigmentation defects, and developmental defects in the arms and hands. PAX3 is a positive regulator of the MITF promoter, and its mutation may lead to defects in melanoblast proliferation during development.
37
What is the significance of SOX10 in melanocyte survival and development?
SOX10 is essential for the development of neural, glial, and melanocyte lineages. Its loss results in a complete absence of melanoblasts and it regulates MITF expression, impacting the survival of postnatal melanocytes and melanoma.
38
Describe the embryonic timeline for melanocyte migration and differentiation from the neural crest.
The timeline for melanocyte migration and differentiation is as follows:
1. E10.5 - 11: MITF is first expressed in melanoblasts after exiting the neural tube.
2. E11.5: Melanoblasts move to the migration staging area (MSA).
3. E12.5: Melanoblasts travel along the dorsolateral pathway and express melanogenic enzymes Dct and TYRP1.
4. E12.5 - 13.5: Melanoblasts enter the epidermis in a synchronous wave.
5. E14.5: Melanocytes express tyrosinase.
6. E15.5: Clusters of epidermal melanoblasts migrate and populate hair follicles.
7. E16.5: Melanocytes display pigmentation.
39
What is the role of SOX2 in melanocyte development?
SOX2 is involved in stem cell maintenance and is one of the four transcription factors required for reprogramming somatic cells to induced pluripotent stem cells. It binds and represses the MITF promoter, and a decrease in SOX2 in Schwann cell precursors leads to an increase in MITF and the emergence of the melanocyte population.
40
How does FoxD3 influence melanocyte fate?
FoxD3 is upregulated early during neural crest development and is crucial for establishing the neural crest lineage. An increase in FoxD3 results in a decrease in MITF, favoring Schwann cell fate, while a decrease in FoxD3 favors melanocyte fate.
41
What is the significance of Ednrb in melanocyte development?
Ednrb is essential for initiating melanogenesis in cultured melanocytes and is an important ligand during melanocyte development. Mutations in Ednrb can lead to Hirschsprung disease, while Edn3 mutations are associated with Waardenburg syndrome and megacolon. Ednrb is necessary for proper melanoblast migration and induces melanocyte proliferation and skin pigmentation.
42
What are the effects of c-Kit mutations on melanocytes?
Heterozygous mutations of c-Kit result in piebaldism, characterized by depigmentation of the forelock and abdominal skin. Mutations in c-Kit or KITLG in mice lead to a loss of melanocytes. c-Kit signaling regulates the survival and differentiation/pigmentation of mature melanocytes.
43
What is the role of Wnt/β-Catenin signaling in melanocyte biology?
Wnt/β-Catenin signaling activates β-catenin, which increases the proliferation and differentiation of melanocytes. It regulates MITF in cultured melanocytes and melanoma cells and potentiates melanoma formation and metastasis.
44
How does Neuregulin/ErbB2/ErbB3 affect melanocyte and Schwann cell fate?
Neuregulin, through the ErbB2/ErbB3 heterodimer tyrosine kinase receptor, controls Schwann cell proliferation, migration, and myelination. It promotes Schwann cell fate while repressing melanocyte fate.
45
What is the function of Rac1 in melanocyte motility and migration?
Rac1 regulates cellular migration through the actin cytoskeleton. Melanoblasts deficient in Rac1 migrate less efficiently, although they can still cross the dermal-epidermal junction and home to hair follicles.
46
What are the two forms of melanin and their origins?
The two forms of melanin are:
| Type | Color | Origin |
|-------------|----------------|----------------|
| Eumelanin | Brown/Black | Derived from Tyrosine |
| Pheomelanin| Yellow/Orange | Derived from Tyrosine |
47
What is the role of tyrosinase in melanin synthesis?
Tyrosinase is a key enzyme that converts tyrosine to dopaquinone, regulating both eumelanogenesis and pheomelanogenesis. Melanin synthesis occurs in the melanosome, a specialized lysosome-related organelle.
48
What are the implications of melanin degradation products on DNA?
Melanin degradation products can escape the melanosome and enter the nucleus, potentially contributing to DNA damage.
49
A researcher observes melanocytes with impaired migration efficiency but normal homing to hair follicles. Which gene mutation might explain this phenotype?
A mutation in Rac1 could explain this phenotype. Rac1 regulates cellular migration through the actin cytoskeleton.
50
A patient with piebaldism has depigmented patches of skin. Which signaling pathway is disrupted, and what is its role in melanocyte biology?
The c-Kit signaling pathway is disrupted. c-Kit regulates the survival, differentiation, and pigmentation of mature melanocytes.
51
A patient with melanoma has a mutation in the PREX2 gene. How does this mutation contribute to melanoma progression?
Mutation of PREX2 promotes melanoma progression by activating Rac1, which regulates cellular migration and metastasis.
52
A patient with familial progressive hyperpigmentation has a polymorphism in KITLG. What is the role of KITLG in melanocyte biology?
KITLG (ligand for c-Kit) regulates the survival, differentiation, and pigmentation of melanocytes.
53
How does the regulation of SOX2 influence the fate of melanocyte precursors and what are the implications for melanoma development?
- SOX2 is crucial for stem cell maintenance and represses the MITF promoter.
- A decrease in SOX2 in Schwann cell precursors leads to an increase in MITF, promoting the emergence of the melanocyte population.
54
What role does the Wnt/β-Catenin pathway play in melanocyte proliferation and melanoma formation?
- The Wnt/β-Catenin pathway activates β-catenin, which increases the proliferation and differentiation of melanocytes.
- It regulates MITF in cultured melanocytes and melanoma cells, indicating its importance in melanocyte biology.
55
Discuss the significance of c-Kit signaling in melanocyte biology and its implications in pigmentation disorders.
- c-Kit signaling is essential for the survival and differentiation of mature melanocytes.
- Heterozygous mutations in c-Kit can lead to piebaldism, characterized by depigmentation in specific skin areas.
56
How does the mutation of PREX1 and PREX2 affect melanoblast migration and melanoma metastasis?
- PREX1 and PREX2 are involved in the regulation of melanoblast migration.
- Loss of function of PREX1 impairs melanoblast migration and melanoma metastasis.
57
What are the two forms of melanin, and how are they synthesized from tyrosine?
- The two forms of melanin are:
- Eumelanin (brown/black)
- Pheomelanin (yellow/orange)
- Both forms are derived from tyrosine through the action of tyrosinase.
58
What are the primary functions of eumelanin in the skin?
Eumelanin serves several key functions in the skin:
- Protection against UV radiation.
- Scavenging of reactive oxygen species (ROS).
- Contribution to skin pigmentation.
59
How does pheomelanin differ from eumelanin in terms of UV protection?
Pheomelanin has distinct properties compared to eumelanin:
- Decreased shielding property against UV radiation.
- Pro-oxidant activity.
60
What is the role of tyrosinase in melanin synthesis?
Tyrosinase plays a crucial role in melanin synthesis by catalyzing the oxidation of tyrosine to dopaquinone. It requires copper for proper function.
61
What are the key structural features of melanosomes as they mature?
As melanosomes mature, they exhibit key structural features:
- Appearance of a parallel fibrillar network.
- PMEL protein.
62
A patient with oculocutaneous albinism has a defect in tyrosinase trafficking. Which proteins are likely involved in this defect?
OCA2 (P-protein) and SCL45A2 are likely involved. They are important for proper tyrosinase trafficking and melanosome maturation.
63
A researcher observes that pheomelanin generates free radicals upon UVA exposure. What are the implications for skin health?
Pheomelanin acts as a pro-oxidant, generating reactive oxygen species (ROS) upon UVA exposure.
64
A patient with a mutation in the ATP7A transporter shows pigmentation defects. What is the role of ATP7A in melanogenesis?
ATP7A delivers copper to the melanosome, which is required for proper tyrosinase function.
65
A patient with a mutation in the TYRP1 gene shows pigmentation defects. What is the role of TYRP1 in melanogenesis?
TYRP1 has distinct catalytic functions in eumelanin synthesis downstream of tyrosinase.
66
A patient with a mutation in the TYRP2/DCT gene shows pigmentation defects. What is the role of TYRP2/DCT in melanogenesis?
TYRP2/DCT has distinct catalytic functions in eumelanin synthesis downstream of tyrosinase.
67
What are the protective roles of eumelanin in human skin against UV radiation?
Eumelanin provides protection against UV radiation by shielding against UV radiation and scavenging UV-induced reactive oxygen species (ROS).
68
How does pheomelanin differ from eumelanin in terms of UV protection and potential risks?
Pheomelanin differs from eumelanin in the following ways:
1. Decreased shielding property against UV radiation.
2. May act as a pro-oxidant.
69
What is the role of tyrosinase in melanin synthesis and what factors are necessary for its function?
Tyrosinase plays a crucial role in melanin synthesis by catalyzing the oxidation of tyrosine to dopaquinone. It requires copper for proper function.
70
What are the key structural features of melanosomes as they mature?
As melanosomes mature, the key structural features include:
1. Development of a parallel fibrillar network.
2. Presence of PMEL (gp100 or silver).
71
What are the characteristics of Stage II melanosomes in melanosome biogenesis?
Stage II melanosomes exhibit increased organization of PMEL amyloid into visible proteinaceous fibrils.
72
What is the role of BLOC and AP3 complexes in melanosome trafficking?
BLOC and AP3 complexes play critical roles in the delivery of proteins to melanosomes.
73
What is a major component of melanosomes?
PMEL is a major component of melanosomes.
74
What are the characteristics of Stage II melanosomes in melanosome biogenesis?
Stage II melanosomes exhibit increased organization of PMEL amyloid into visible proteinaceous fibrils, which push the intraluminal vesicles outward to fuse with the melanosome membrane.
75
What is the role of BLOC and AP3 complexes in melanosome trafficking?
BLOC and AP3 complexes play critical roles in the delivery of melanosomal cargoes in recycling endosomes, facilitating the transport of melanogenic enzymes to the maturing melanosome.
76
How are Stage IV melanosomes transferred to keratinocytes?
Stage IV melanosomes are first transferred to the dendrite tips by kinesin-mediated microtubule-dependent anterograde transport, and upon reaching the actin-rich peripheral dendrite tips, they are captured by a receptor complex for eventual transfer to the keratinocyte.
77
What is the significance of Rab27a in the transfer of melanosomes?
Rab27a is incorporated into the melanosome membrane and plays a crucial role in the transport and retention of melanosomes on the actin cytoskeleton, facilitating their transfer to neighboring keratinocytes.
78
What happens during the final step of melanosome maturation?
The final step involves the fusion of cargo-containing vesicles and tubules with the developing melanosome, which requires SNARE proteins for membrane fusion, specifically VAMP7 and BLOC-3 for recycling.
79
What is the role of BLOC-1 in melanosome biogenesis?
BLOC-1 coordinates microtubule- and actin-dependent machineries to form and stabilize recycling endosomal tubules, which are required for transferring cargoes to melanosomes. Dysfunction leads to pigmentary abnormalities.
80
What could be the consequence of improper formation of fibrillar PMEL in stage II melanosomes?
Improper formation of fibrillar PMEL in stage II melanosomes can disrupt melanin synthesis and lead to pigmentation abnormalities.
81
What is the role of Rab27a in the transfer of melanosomes to keratinocytes?
Rab27a is incorporated into the melanosome membrane and, along with melanophilin and MyosinVa, facilitates transport and retention of melanosomes on the actin cytoskeleton for transfer to keratinocytes.
82
What changes occur in tyrosinase activity in stage IV melanosomes?
In stage IV melanosomes, tyrosinase activity and melanin synthesis have ceased.
83
Which proteins might be defective if melanosomes are not properly transferred to keratinocytes?
Defective proteins could include Rab27a, melanophilin (Mlph), or MyosinVa, which are involved in melanosome transport and retention on the actin cytoskeleton for transfer to keratinocytes.
84
What is the role of BLOC-2 in melanosome biogenesis?
BLOC-2 directs recycling endosomal tubular transport intermediates to maturing melanosomes, promoting melanogenic cargo delivery. Dysfunction leads to pigmentary abnormalities.
85
What is the role of VAMP7 in melanosome cargo delivery?
VAMP7 is the SNARE protein responsible for BLOC-1-dependent delivery of TYRP1 to the melanosome.
86
What process occurs in stage III melanosomes?
In stage III melanosomes, melanogenic enzymes are delivered, and melanin synthesis proceeds, leading to increased pigmentation.
87
What is the role of AP3 in melanosome biogenesis?
AP3 is important for sorting cargo proteins bound for melanosomes. Dysfunction leads to pigmentary abnormalities.
88
What could be the underlying cause if stage I melanosomes are not forming properly?
Stage I melanosomes form independently of the endosomal sorting complex required for transport (ESCRT) machinery. A defect in this process could disrupt their formation.
89
What could be the cause if stage II melanosomes are not properly receiving melanogenic enzymes?
A defect in the recycling endosome compartment, which plays a key role in delivering melanogenic enzymes to maturing melanosomes, could be the cause.
90
What is the role of BLOC-3 in melanosome cargo recycling?
BLOC-3 is required for the recycling of VAMP7 after cargo delivery to the melanosome.
91
What transport mechanisms are involved in the transfer of stage IV melanosomes to keratinocytes?
Stage IV melanosomes are transferred to dendrite tips by kinesin-mediated microtubule-dependent transport and then captured by a receptor complex for transfer to keratinocytes.
92
What could be the underlying cause if melanosomes in stage III are not properly melanized?
A defect in the delivery of melanogenic enzymes or a disruption in melanin synthesis could prevent proper melanization in stage III melanosomes.
93
What are the key stages of melanosome development and their characteristics?
| Stage | Characteristics |
|-------|----------------|
| Stage I | Form independently of ESCRT machinery. |
| Stage II | Increased organization of PMEL amyloid into visible proteinaceous fibrils; pushes intraluminal vesicles outward to fuse with the melanosome membrane. |
| Stage III | Become increasingly pigmented as melanogenic enzymes are delivered and melanin synthesis proceeds. |
| Stage IV | Fully pigmented; tyrosinase activity and melanin synthesis have ceased. |
| Pheomelanosomes | Smaller, spherical in shape, with a granular and microvesicular matrix, and microgranular and spotty melanization.
94
How do BLOC and AP3 complexes contribute to melanosome trafficking?
- **BLOC complexes**:
- Play critical roles in the delivery of melanosomal cargoes in recycling endosomes.
- BLOC 1 coordinates microtubule- and actin-dependent machineries for proper formation and stabilization of recycling endosomal tubules.
- BLOC 2 directs recycling endosomal tubular transport intermediates to maturing melanosomes.
- **AP3 complex**:
- Important for sorting cargo proteins bound for melanosomes.
95
What is the role of Rab27a and melanophilin in the transfer of melanosomes to keratinocytes?
- **Rab27a**:
- Incorporated into the melanosome membrane by a hydrophobic geranylgeranyl tail.
- **Melanophilin (Mlph)**:
- Binds Rab27a and serves as a linker to the actin-binding motor protein MyosinVa (MyoVa).
- Facilitates transport and retention of melanosomes on the actin cytoskeleton, allowing for their transfer to neighboring keratinocytes.
96
What role does Keratinocyte growth factor (KGF) play in the transfer of melanosomes?
Keratinocyte growth factor (KGF) promotes **phagocytosis** and **transfer** of melanosomes from melanocytes to keratinocytes.
97
How does the size and distribution of melanosomes differ between light-skinned and dark-skinned individuals?
In light-skinned individuals, melanosomes are:
- Smaller
- Grouped in membrane-enclosed clusters of 4-8 melanosomes
In dark-skinned individuals, melanosomes are:
- Larger
- More numerous
- Distributed individually
- Keratinocytes degrade melanosomes more slowly.
98
What is the significance of MC1R signaling in melanocyte function?
MC1R signaling plays a critical role in determining whether a melanocyte produces predominantly **eumelanin** or **pheomelanin**. Loss-of-function variants of MC1R are associated with the 'red hair phenotype', characterized by red hair, fair skin, and inability to tan.
99
What is the canonical agonist for MC1R and its role in pigmentation?
The canonical agonist for MC1R is **alpha-melanocyte stimulating hormone (α-MSH)**. It is a key regulator of vertebrate pigmentation, derived from the proteolytic processing of its precursor **proopiomelanocortin (POMC)**.
100
Which receptor mutation is likely responsible for a patient with red hair and fair skin who is unable to tan?
A mutation in the MC1R receptor is responsible. Loss-of-function variants of MC1R lead to reduced eumelanin production and increased pheomelanin, resulting in red hair, fair skin, and inability to tan.
101
What differences are observed in keratinocytes of dark-skinned individuals compared to light-skinned individuals?
In dark-skinned individuals, melanosomes are distributed individually and degraded more slowly in keratinocytes compared to light-skinned individuals, where melanosomes are smaller and grouped in clusters.
102
What contributes to the rapid degradation of melanosomes in light-skinned individuals?
In light-skinned individuals, melanosomes are grouped in membrane-enclosed clusters, which facilitates their rapid degradation during keratinocyte terminal differentiation.
103
What role does keratinocyte growth factor (KGF) play in the transfer of melanosomes to keratinocytes?
Keratinocyte growth factor (KGF) promotes **phagocytosis** and the **transfer** of melanosomes from melanocytes to keratinocytes.
104
What is the significance of MC1R signaling in melanocyte function?
MC1R signaling is critical in determining whether a melanocyte produces predominantly **eumelanin** or **pheomelanin**. Loss-of-function variants of MC1R are associated with the 'red hair phenotype', characterized by red hair, fair skin, and inability to tan.
105
Describe the process of melanosome trafficking within keratinocytes and its protective role against UV damage.
After transfer to the keratinocyte, melanosomes are transferred by **dynein-mediated retrograde transport** to a perinuclear location ('nuclear capping') to protect basal keratinocytes from **UV-induced DNA damage**.
106
What role does MITF play in melanogenesis?
MITF (Microphthalmia-associated transcription factor) is a key regulator of melanogenesis, stimulating the production of melanin in melanocytes. It is activated by various signaling pathways, including those influenced by UV radiation and growth factors.
107
How does UV radiation affect melanocyte activity and pigmentation?
UV radiation stimulates melanocyte activity by increasing the expression of POMC, leading to the production of a-MSH, which activates MC1R signaling. This results in the activation of MITF and subsequent melanogenesis, contributing to skin tanning.
108
What are the two components of inducible pigmentation after UV exposure?
The two components of inducible pigmentation after UV exposure are:
1. **Immediate Tanning**: Occurs within minutes to hours after sun exposure, primarily due to UVA radiation.
2. **Delayed Tanning**: Peaks about 3 days to 1 week after sun exposure, associated with UVB and shorter wavelength UVA radiation.
109
What is the significance of MC1R mutations in relation to melanoma risk?
MC1R mutations are associated with an increased risk of melanoma, particularly in individuals with red hair and fair skin. These mutations can lead to a 2- to 4-fold increase in melanoma risk due to the production of pheomelanin, which generates reactive oxygen species (ROS) that can damage DNA.
110
What factors regulate human pigmentation according to the content?
Factors regulating human pigmentation include:
- **Melanocyte Signaling (MAKI-Sig)**: Involves MC1R, ASIP, and KITLG.
- **Melanin Synthesis (Syn-TOTS-is)**: Refers to the biochemical pathways involved in the production of melanin.
111
What pathway is activated when UV radiation increases pigmentation in keratinocytes?
The MC1R-MITF pathway is activated. UV radiation stimulates POMC expression in keratinocytes, leading to increased α-MSH production, which activates MC1R on melanocytes. This triggers MITF activation and melanogenesis.
112
How does decreased TGFβ1 production in keratinocytes affect melanogenesis?
Decreased TGFβ1 production leads to increased MITF pathway stimulation, resulting in enhanced melanogenesis.
113
How does a mutation in MC1R affect DNA repair mechanisms in a patient with red hair and increased melanoma risk?
MC1R mutations impair the DNA nucleotide excision repair (NER) pathway and increase UVB-mediated degradation of the tumor suppressor PTEN, contributing to melanoma risk.
114
What protein might be overexpressed if pheomelanin synthesis is increased in a mouse model?
Overexpression of agouti protein (ASIP) could increase pheomelanin synthesis by antagonizing MC1R signaling.
115
What is the downstream effect on melanocytes when UV radiation stimulates POMC expression in keratinocytes?
POMC expression leads to increased α-MSH production, which activates MC1R on melanocytes, triggering MITF activation and melanogenesis.
116
How does a mutation in the MC1R gene affect melanin synthesis in a patient with increased melanoma risk?
MC1R mutations reduce eumelanin production and increase pheomelanin, which generates reactive oxygen species (ROS) and increases melanoma risk.
117
What role does MITF play in melanogenesis and how is it regulated by various factors?
**MITF** (Microphthalmia-associated transcription factor) is crucial for **melanogenesis**. It is regulated by:
1. **Agouti protein**: Acts as an antagonist, with mutations leading to increased pheomelanin production.
2. **Phosphodiesterase D4 (PDED4)**: Activated by MITF, it degrades cAMP, serving as a negative feedback regulator.
3. **PPAR-gamma coactivators (PGC-1alpha and PGC-1beta)**: Stimulate melanogenesis through upregulation of MITF.
4. **TGFb pathway**: TGFb1 negatively regulates MITF, while UV radiation decreases TGFb1 production, leading to increased MITF stimulation and melanogenesis.
118
How does UV exposure lead to immediate and delayed tanning?
UV exposure induces two types of tanning:
1. **Immediate Tanning**:
- Occurs within minutes to hours after exposure.
- Mediated by **UVA radiation**.
2. **Delayed Tanning**:
- Peaks about 3 days to 1 week after exposure.
- Mediated by **UVB and shorter wavelength UVA radiation**.
119
What histological changes are observed in darker-skinned individuals after UV exposure?
Histological Changes in Darker-skinned Individuals:
- Increased number of epidermal melanocytes.
- Enhanced melanocyte dendricity.
- Greater transfer of melanosomes to keratinocytes and increased melanization of individual melanosomes.
120
What is the significance of MC1R variants in relation to melanoma risk and how do they affect pigmentation?
MC1R variants are associated with an increased risk of melanoma, particularly in individuals with red hair and fair skin. These mutations can lead to reduced eumelanin production and increased pheomelanin, resulting in a higher melanoma risk.
121
What is Delayed Tanning?
Delayed tanning peaks about 3 days to 1 week after exposure and is mediated by UVB and shorter wavelength UVA radiation.
122
What are the histological changes in darker-skinned individuals related to tanning?
In darker-skinned individuals, there is an increased number of epidermal melanocytes, enhanced melanocyte dendricity, and greater transfer of melanosomes to keratinocytes with increased melanization of individual melanosomes.
123
What is the significance of MC1R variants in relation to melanoma risk?
MC1R variants are significant in melanoma risk: hypomorphic MC1R variants promote red hair and are strong risk factors for melanoma, leading to a 2- to 4-fold increased risk.
124
How do missense variants of MC1R affect melanoma risk?
Missense variants of MC1R, while less strongly associated with red hair, still increase melanoma risk.
125
What role does pheomelanin play in melanoma risk?
Pheomelanin increases melanoma risk through the generation of reactive oxygen species (ROS) via UV-dependent and independent mechanisms.
126
What is the protective role of wildtype MC1R?
Wildtype MC1R protects the tumor suppressor PTEN from UVB-induced degradation, while MC1R deficient melanocytes show increased UVB-mediated PTEN degradation, promoting melanoma.
127
What is the role of the gene SLC24A5 in human pigmentation?
SLC24A5 correlates with lighter skin color in other populations.
128
How does the gene TPCN2 affect melanosomes?
TPCN2 is involved in regulating melanosome pH and size.
129
What is the function of the IRF4 gene in pigmentation?
IRF4 regulates human pigmentation and acts with MITF to stimulate the transcription of tyrosinase.
130
What is the significance of the BNC2 gene in pigmentation?
BNC2 is a novel gene associated with human pigmentation, although its specific role is less defined compared to others.
131
How does the gene IRF4 contribute to human pigmentation?
IRF4 regulates human pigmentation and acts with MITF to stimulate the transcription of tyrosinase, which is crucial for melanin production.
132
What is the function of TPCN2 in melanocytes?
TPCN2 is involved in regulating melanosome pH and size, which can affect the overall pigmentation process.
133
What are the implications of the gene BNC2 in pigmentation?
BNC2 is a novel gene that may play a role in the regulation of pigmentation, although its specific functions are less well-defined compared to other genes mentioned.
