The establishment of boundaries between cells and tissues is a critical feature of pattern forma- tion in every animal embryo. These same boundaries must be maintained and new ones established as organogenesis and growth continue during later post-embryonic development. Still later in the adult, the maintenance of cell and tissue boundaries is essential for normal homeo- stasis. The mechanisms underlying such boundaries are thus of fundamental biological significance. Yet these same mechanisms also have profound implications for a variety of genetic diseases, cancers, in which boundary constraints are lost, and regenerative contexts, in which boundaries must be formed anew. The goal of this project is to understand the genetic and cellular mechanisms underlying cellular boundaries in post-embryonic vertebrate development. To this end, these studies will employ an especially tractable example of boundary formation, the development and maintenance of adult pigment stripes in the zebrafish. Previous efforts demonstrated that interactions between different classes of pigment cells are essential for normal stripes to develop, though the genes and cell behaviors involved have yet to be elucidated. In proposed Aim 1, time-lapse imaging will be used to visualize cell-cell interactions during stripe development and regeneration, and to test the hypothesis that direct, short-range and long- range contacts are involved.
Aim 2 will test functions of previously isolated and new genes for which mutants have boundary-defective phenotypes. In addition to normal development, these studies will extent to imaging the behavior of melanoma cells and how invasion and metastasis by these cells is affected by genetic background.
Aim 3 will build upon earlier studies by testing a new class of pigment cell for its function in boundary formation, as well as the role of a candidate genetic pathway for mediating these effects. Finally, Aim 4 will identify new genes and pathways contributing to stripe boundary formation through the analysis of candidate pathways as well as comparisons of whole transcriptomes between defined pigment cell populations across stages and genetic backgrounds. These studies will provide valuable new insights into the genetics of pigment cell boundary formation and melanoma progression, as well as the logic of boundary forming mechanisms more generally.

Public Health Relevance

The establishment and maintenance of cell and tissue boundaries is critical for normal development. In turn, discovering the mechanisms underlying such processes will have important implications for human health and disease, as well as efforts to stimulate tissue regeneration following traumatic injury. These studies in this proposal focus on pigment cells, which in humans are associated with a variety of disorders including melanoma. Our research will shed new light on the genes and cell behaviors responsible for the formation and maintenance of boundaries during development, and how these mechanisms interact with the neoplastic state.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM096906-04
Application #
8725517
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Hoodbhoy, Tanya
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Washington
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98195
Inoue, Shinya; Kondo, Shigeru; Parichy, David M et al. (2014) Tetraspanin 3c requirement for pigment cell interactions and boundary formation in zebrafish adult pigment stripes. Pigment Cell Melanoma Res 27:190-200
McMenamin, Sarah K; Bain, Emily J; McCann, Anna E et al. (2014) Thyroid hormone-dependent adult pigment cell lineage and pattern in zebrafish. Science 345:1358-61
Patterson, Larissa B; Bain, Emily J; Parichy, David M (2014) Pigment cell interactions and differential xanthophore recruitment underlying zebrafish stripe reiteration and Danio pattern evolution. Nat Commun 5:5299
Patterson, Larissa B; Parichy, David M (2013) Interactions with iridophores and the tissue environment required for patterning melanophores and xanthophores during zebrafish adult pigment stripe formation. PLoS Genet 9:e1003561