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The role of SASH1 in skin pigmentation

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Melanocytes are pigment producing cells that protect our skin from solar ultraviolet radiation (UVR). We identified a novel gene, SASH1, involved in an inherited hyperpigmentation phenotype, with increased melanocyte number and pigmentation in skin and altered UV response of keratinocytes. SASH1 is a potential tumor suppressor; however, not much is known about the functions of SASH1 in melanocytes, keratinocytes, or pigmentation. Thus, understanding the function of this novel and uncharacterized human pigmentation gene and etiology of this unique disorder will lead to new insight in melanocyte, pigmentation, and keratinocyte biology. Based on our preliminary results from human patients, in vitro and zebrafish, we hypothesize that SASH1 functions in UV-induced pigmentation involving melanocytes and keratinocytes, as well as in the development, differentiation and maintenance of melanocytes. To test our hypotheses, we will use an innovative combination of powerful and complementary cell culture system and zebrafish models. Mono-cell culture systems are best to study the biological functions in individual cell types, and 3D skin- reconstruct cell culture systems are best to study communication between cell types, such as in skin. Due to their conserved pigmentation pathways with mammals, the availability of assays, and the transparency of all development stages, zebrafish is one of the best models for studying development of melanocytes. For this R03, we will focus on studying the functions of wild type SASH1 and establishing protocols, models, and preliminary data for future detailed investigations in a R01 project. Aim 1 will define the roles of SASH1 in melanocytes and keratinocytes. Both melanocytes and keratinocytes are important for skin pigmentation, and our data suggest that SASH1 functions in both cell types. We will further: 1) define the effects of SASH1 knockdown in melanocytes on pigmentation, differentiation, cellular aging, cell growth and survival; 2) determine which melanogenic factor(s) are regulated by SASH1 upon UVR in keratinocytes; and 3) test SASH1's role in a 3D skin reconstruct system for modeling human skin in vitro. Aim 2 will characterize the function of sash1a in the development and regeneration of melanocytes in zebrafish. Our clinical data suggest that SASH1 regulates melanocyte regeneration, and sash1a knock-down in zebrafish disrupts melanocyte embryonic development. We will further 1) test how sash1a knockdown affects melanocyte development, by examining neural crest progenitor specification, migration, and survival; 2) determine whether sash1a knockdown affects melanocyte regeneration following melanocyte-specific ablation; and 3) define the pathways regulated by sash1a using RNA-Seq. In summary, we will combine two complementary models to study the function of a novel and uncharacterized pigmentation gene in vitro and in vivo. A future R01 application will build on R03 preliminary data to further elucidate the function of SASH1 in the UV protective nature of skin.
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