SASH1’s functions in pigmentation and melanocyte stem cell maintenance in humans and mice

Summary: Abstract Body: SASH1 is a novel pigmentation gene in humans, with mutations linked to inherited pigmentation disorders. Understanding the function of SASH1 could provide new insights into pigmentation and melanocyte biology, paving the way for new treatments for melanocyte-related diseases. This study aims to elucidate the role of SASH1 in regulating pigmentation and melanocyte lineage using in vitro, human, and mouse models. In cell cultures, wild type SASH1, but not mutated SASH1 (S519N) promotes stem-like characteristics. In humans, individuals carrying SASH1-S519N display accelerated hyper- and hypo-pigmentation in the skin and early hair graying. These results indicate accelerated aging in human melanocyte stem cells, linking both gain and loss of pigmentation to their dysfunction in the same individuals. In B6 mice, knockout of SASH1 results in a persistent dilute coat color from early postnatal stages. The dilute appearance is caused by significantly increased length of unpigmented hair tips (p<0.01), leading the animal to appear gray. Histological assessment shows the occurrence of clumped pigment at the hair bulbs, suggesting SASH1’s role in melanosome transport. Interestingly, while SASH1 knockout does not accelerate waxing-induced hair graying, acute stress increases the amount of white hair, highlighting SASH1's role in melanocyte stem cell maintenance under specific conditions. Further mechanistic studies with cell culture are ongoing. In conclusion, our studies indicate the importance of assessing hair pigmentation loss in clinical evaluations of hyperpigmentation in human patients. SASH1 is critical for pigmentation and melanocyte stem cell maintenance in both humans and mice. Nabanita Mukherjee¹, Karoline Lambert¹, Landon Tomb¹, Christopher Clements¹, Barbara Fox¹, Laura Hoaglin¹, Theresa R. Pacheco¹, Klaus-Peter Janssen², Yiqun G. Shellman^{1, 3} 1. University of Colorado Anschutz Medical Campus School of Medicine, Aurora, CO, United States. 2. Surgery, Technische Universitat Munchen, Munich, BY, Germany. 3. VA Eastern Colorado Health Care System, Aurora, CO, United States. Pigmentation, Melanoma, and Melanoma Immune Surveillance