More than skin deep: Utilising an ATG16L1 mouse model to study skin homeostasis and pigmentation dynamics

Conway, Shannon Colleen (2024) More than skin deep: Utilising an ATG16L1 mouse model to study skin homeostasis and pigmentation dynamics. Doctoral thesis, University of East Anglia.

Preview

PDF Download (17MB) | Preview

Abstract

The skin, comprising the epidermis, dermis, and hypodermis, serves as a barrier against environmental and biological threats. This barrier function relies on the layered structure and constant turnover of the epidermis. Within the epidermis, melanocytes and keratinocytes are crucial for photoprotection and barrier integrity, respectively.

Autophagy is a highly conserved self-eating process that is initiated in response to nutrient starvation, delivering damaged intracellular proteins and organelles to lysosomes for degradation. It is essential for skin barrier function, melanogenesis, and melanosome processing. LC3-associated phagocytosis (LAP) is a related process that utilises some autophagy components, conjugating LC3 to single-membraned phagosomes. LAP plays a role in the innate immune response, protecting tissue from pathogens and aiding in tissue homeostasis. Its versatile capability to engulf diverse cargoes, spanning from fungi and viruses to apoptotic cells, emphasises its significance in cellular physiology. So far, the relationship between skin homeostasis, pigmentation, and LAP remains unclear.

To examine this relationship, I utilised the ATG16L1ΔWD mouse model (ΔWD), which harbours a mutated WD domain in ATG16L1, rendering it LAP-deficient but autophagy-competent. This study aimed to evaluate the role of LAP in skin homeostasis and determine if LAP-defective mice (ΔWD) exhibit a cutaneous phenotype. Additionally, it investigated the involvement of LAP in melanosome trafficking and processing in primary cultures of mouse skin keratinocytes.

Findings revealed that ΔWD mice exhibit no signs of impaired barrier function, yet aged ΔWD mice demonstrated an accelerated decline in biomechanical properties compared to littermate controls. Assessment of the melanosome dynamics in ΔWD primary keratinocyte cultures indicated that melanosomes are internalised and trafficked to the supranuclear region in keratinocytes and subsequently stored in lysosomal compartments, surrounded by LC3. This suggests that melanosomes are processed in keratinocytes in an autophagy-driven manner, with melanin later stored in the lysosome for long-term storage.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Science > School of Chemistry, Pharmacy and Pharmacology
Depositing User:	Chris White
Date Deposited:	17 Mar 2025 11:50
Last Modified:	17 Mar 2025 11:50
URI:	https://ueaeprints.uea.ac.uk/id/eprint/98759
DOI:

Downloads

Actions (login required)

View Item