Lecture 12 - Pigmentation

What is the pathway for melanocyte migration during development?

• Arise from neural crest (ectoderm) and migrate out

• Choose dermis or cross into epidermis

• Epidermis → hair follicle or interfollicular epidermis (melanocyte)

2. How is melanin made and transferred to keratinocytes?

• made by melanosomes from the endosomes - take up melanosomal proteins

• melanosomes are phagocytosed into keratinocytes from dendrites of melanocytes

3. Why and how does skin tan in response to sunlight?

• UV light induces DNA damage (double-stranded breaks)

• p53 stabilizes DSB and upregulates POMC

• POMC gets cleaved into signalling molecules alpha-MSH and beta-endorphin

• Alpha-MSH binds Mc1R receptor on melanocytes to upregulate production of melanin

• melanin acts as optical shield, protects DNA damage in skin cells

4. What are the key genes that regulate a) melanin production and b) melanocyte development?

5. Melanin production

   • MC1R

   • TYR

   • TYRP1

   • SLC24A5

   • IRF4

6. Melanocyte development (genes that impact melanocyte migration)

   • Transcription factors

     • Pax3

     • Sox10

     • Mitf

     • Snai2

   • Receptor/ligand genes

     • ETB - endothelian receptor B

     • ET3 - endothelian 3 ligand

5. What is the difference between a melanocyte and a melanosome?

• melanocyte - melanin producing CELL

• melanosome - organelle with melanocytes that produces melanin

6. How is pH related to melanin synthesis?

• determines which type of melanin is made (eumelanin vs pheomelanin)

• tyrosinase more active at low pH

7. What has GWAS told us about normal skin colour variation?

• complex trait - spectrum of skin colours

• highly polygenic trait - many associated loci and SNPs (36 SNPs at 16 loci)

• under strong selective pressure, colour changes when humans adapt to new environment

• barely know anything about skin colour genetics]

8. What causes blue eye colour (two ways discussed in class)?

• lack of pigment in the outer layer of iris

  • light is reflected back and blue light scatters

• SNP on chr15 (C allele)

  • people with blue eyes have CC or TC genotype

  • in enhancer region of OCA2 gene

    • CC/TC genotype prevents enhancer binding → low levels of OCA2 → low levels of melanocytes

  • influences ability of TFs to loop enhancer over OCA2 promoter (OCA2 encodes ion transporter found in melanosomes)

9. What causes albinism?

• normal number of melanocytes but not enough melanin

• decreased or absent melanin synthesis due to mutations in pathway

  • tyr, tyrp1, oca2, slc45A2

10. What is the mechanism that produces pigmentary abnormalities in Waardenburg syndrome?

• areas of iris, hair and skin are hypo-pigmented - lack melanocytes

  • thought to be failure to make enough melanocytes or failure of migration

  • some parts of body are harder to migrate to or are last on the route (belly)

    • more likely to be left without pigment if there is already low precursors/migration

• once migration is over, melanocytes don’t move, empty spaces don’t get filled

1. What causes different skin colours

   • differences in amount of melanin within melanosomes

   • ratio of two types of melanin, eumelanin (brown), pheomelanin (red/yellow)