Abstract

The neural crest is a transient, multipotent cell population unique to vertebrates that gives rise to diverse lineages, including craniofacial cartilage, peripheral neurons, glia, and pigment-producing melanocytes. Proper specification and differentiation of neural crest derivatives are orchestrated by tightly regulated gene regulatory networks, and disruption of these developmental programs can lead to congenital disorders and malignancies. Melanocytes, derived from the neural crest, are best known for their role in skin pigmentation but also contribute to homeostasis and specialized functions in the eye, ear, and heart. These cells produce melanin to protect tissues from ultraviolet radiation and oxidative damage, and they play key roles in immune signaling, tissue structure, and sensory function. However, melanocytes are also highly responsive to environmental stress and intrinsically vulnerable to transformation. In melanoma, the most aggressive form of skin cancer, melanocytes acquire oncogenic mutations and reactivate neural crest-associated gene programs that promote dedifferentiation, invasion, and therapeutic resistance. This dissertation investigates the molecular underpinnings of melanocyte development and melanoma progression, with a focus on two transcription factors, SOX10 and ETV4, that regulate neural crest and melanocyte biology. SOX10, a core component of the melanocyte lineage gene regulatory network, is indispensable for melanocyte specification, survival, and pigment gene expression. Beyond its developmental roles, SOX10 functions as a major lineage dependency in melanoma, maintaining proliferative identity, promoting phenotypic plasticity, and contributing to drug resistance. To define the molecular mechanisms underlying SOX10 function, this work employs proximity-dependent biotinylation (miniTurbo) to map the human SOX10 interactome in melanoma cells, revealing novel co-regulators and chromatin-associated partners that support its oncogenic activity. ETV4, a member of the ETS family of transcription factors, is broadly expressed in embryogenesis and cancer but has not been well studied in melanocyte lineages. Using a zebrafish model of melanoma, this dissertation shows that etv4 overexpression delays melanocyte differentiation during development and suppresses melanoma formation in adults. Together, these studies illuminate the roles of SOX10 and ETV4 in melanocyte biology and melanoma progression. By uncovering lineage-specific transcriptional mechanisms and protein interactions, this work contributes to a deeper understanding of melanocyte plasticity and identifies potential targets for therapeutic intervention in melanoma and pigmentary disorders.

Committee Chair

Charles Kaufman

Committee Members

David Chen; Lavinia Sheets; Lilianna Solnica-Krezel; Michael Major

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Developmental, Regenerative, & Stem Cell Biology)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

5-6-2025

Language

English (en)

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