Plastic Surgery Research Council
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PSRC 60th Annual Meeting
Program and Abstracts

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Understanding Melanoma Pathogenesis By Elucidating The Gene Regulatory Network Of Melanocyte Progenitors.
Stefanie Monica, BS1, Richard Harland, PhD2, Eric Liao, MD,PhD1.
1Massachusetts General Hospital, Boston, MA, USA, 2University of California, Berkeley, Berkeley, CA, USA.

PURPOSE:
Melanoma is the most rapidly growing cancer owing to improved detection and increasing harmful UV exposure in the general population. Current understanding of melanoma pathogenesis suggests that melanoma cancer field arises from reinitiation of the embryonic developmental program in an aberrant fashion. Understanding how melanocytic progenitors arise form the trunk neural crest is mandatory to inform melanoma pathogenesis and advance its treatment. While we and others have detailed embryonic lineage map of cranial neural crest cells (NCCs) that elaborate into the craniofacial skeleton, the trunk NCCs that give rise to melanocyte progenitors have been understudied. In this work, we use the zebrafish model in order to construct the trunk NCC lineage map and elucidate the gene regulatory network (GRN) regulating trunk NC specification, migration and differentiation.
METHODS:
Lineage analysis of trunk NCC was carried out by cell labeling using a sox10:kaede transgenic line, where the sox10 promoter confers lineage restriction of the photoconvertible protein kaede to NCCs, beginning from the onset of NC delamination from the neural tube to subsequent derivatives. This transgenic line enables us to identify in vivo and isolate in vitro precise trunk NC populations that will give rise to specific derivatives. We analyzed expression profiles of genes of interest by wholemount RNA in situ hybridization.
RESULTS:
As a first step to analyze the GRN regulating trunk NCC, we used sox10:kaede fish to construct a lineage map of the trunk NCCs. Photoconversions were performed prior to NCC delamination and migration and analyzed after differentiation was complete. The photoconversions demonstrate the various trunk NC derivatives arise from distinct areas along the anteroposterior axes. Interestingly, we find that two unique neural crest-derived pigment cells, melanocytes and iridophores, do not originate from the same position in the developing embryo. We next sought to determine how perturbations in signaling pathways known to be involved in early stages of NC formation, such as Wnt signaling or BMP signaling, affect the migration and differentiation, and ultimately the lineage map, of the trunk NCCs. This work, in conjunction with single cell RNA sequencing will elucidate the molecular program that directs trunk NC development and address broader questions in cellular specification and differentiation.
CONCLUSION:
We demonstrate that seemingly similar NC-derived tissues arise from very distinct positions along the anteroposterior axis of the developing vertebrate embryo regulated by different genes. The trunk NC lineage map is an invaluable tool for developmental biologists investigating development of cell types that originate from the trunk NC, such as dorsal root ganglia, enteric neurons, adrenal medulla, and aortic nerve clusters, in addition to the melanocytic progenitors. Further, this work has the potential to elucidate the pathogenic nature of melanoma and therefore enable better molecular oncotyping and novel treatment modalities.


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