Investigator: Larissa Patterson, Rhode Island College
Theme: Cancer
Title: Genetic analysis of Kita signaling during melanocyte migration
Award: SURF PUI Training Award (2022-2024)

Abstract: The KIT receptor tyrosine kinase is required for many aspects of melanocyte behavior including melanogenesis, proliferation, migration, and survival. Mutations resulting in constitutive activation of KIT promote the formation and progression of certain types of melanoma. Mutations in KIT are dispersed across the coding region suggesting that KIT mutations are not functionally equivalent and affect distinct aspects of tumorigenesis.

The role of KIT in melanocyte development is highly conserved. In zebrafish Kita mutants, melanocytes differentiate but fail to migrate to appropriate locations and eventually die. The roles of Kita in migration and survival are genetically and temporally distinct, but the intracellular signaling and molecular mechanisms that mediate specific cellular responses are poorly characterized. A recent CRISPR/Cas9 screen identified two genes, protein tyrosine kinase 2 beta b (ptk2bb) and Rho GTPase activating protein 1 (arhgap1), that may act downstream of Kita during zebrafish embryonic melanocyte. Aim 1 of this study will test the hypothesis that ptk2bb acts downstream of Kita to promote melanocyte survival and homeostasis and Aim 2 will test the hypothesis that arhgap1 acts to promote melanocyte proliferation. Both hypotheses will be tested through the analysis of loss of function and over-expression phenotypes during zebrafish melanocyte migration and pattern formation. In situ hybridization will be used to determine the temporal and spatial expression patterns of these genes and epistatic (double mutant) analysis will also be used examine interactions with Kita. Together these proposed studies will provide insight into the intracellular mechanisms that control melanocyte behaviors during normal development and could provide important therapeutic targets to slow melanoma progression. This research is well suited for undergraduates and will allow Rhode Island College students to gain expertise with modern developmental biology techniques and experimental approaches.

Relevance: Melanoma is a serious form of skin cancer that develops from cells called melanocytes. Melanoma is the deadliest type of skin cancer since it is the most likely to metastasize and spread to other parts of the body. Understanding the intracellular signaling pathways that regulate melanocyte behaviors during embryonic development can provide valuable insight into the molecular mechanisms of malignant melanoma.