DEVELOPMENTAL ORIGINS AND HOMEOSTATIC MECHANISMS UNDERLYING ADULT PHENOTYPES

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PROJECT SUMMARY Mechanisms underlying the origin and maintenance of adult form, and naturally occurring variation in adult form, remain poorly understood. The research program described here seeks to elucidate how gene activities are translated through cellular behaviors into specific morphological outcomes at adult stages. Such knowl- edge will provide insights into essential aspects of post-embryonic patterning and morphogenesis. It will also have impacts relevant to human health in the realms of congenital deformity, aging, cancer and regenerative medicine. This program focuses on adult pigmentation of zebrafish and its relatives. Pigment cell lineages in vertebrates originate in the embryonic neural crest and depend on precise mechanisms to segregate fate and regulate differentiation in a context of extensive morphogenesis, and particularly migration. Besides sharing these features with other neural crest derivatives, adult pigment cells are interesting because they organize into a diverse array of naturally occurring patterns; because they arise from latent progenitors—and so can provide insights into stem cells biology more generally; and because these lineages give rise to melanoma, representing a profound failure of adult homeostasis and growth control with deadly consequences. The work proposed here will build on our prior efforts that identified distinct lineages of pigment cells having distinct ge- netic and endocrine requirements, as well as our discovery of several types of interactions among pigment cell classes that are needed to establish, implement, and maintain species-specific forms of adult pattern. Our goals in the coming years are to elucidate: (i) genetic and cellular mechanisms of pigment cell interactions and differential dependencies on thyroid hormone during adult stripe development in zebrafish; (ii) the ways in which pigment cell lineages, and particularly latent stem cells, are regulated during adult homeostasis, and how defects in these processes contribute to melanoma susceptibility and progression; and (iii) how previously unstudied pigment cell fates are regulated, and pigment cells organized, to generate species-specific pattern variants. Towards these ends we will use a suite of approaches, including state of the art imaging and modern methods of interrogating gene activities, and we will exploit not only stripes of zebrafish but also the pattern diversity of close zebrafish relatives, to which the same methods are readily applied. Together our efforts will provide novel insights into the genetic and cellular bases for adult forms of this neural crest derived trait, with implications both basic and translational. !1