The long-term objective of this work is to identify genetic, cellular, and endocrine mechanisms required for post-embryonic development in vertebrates. This proposal focuses on metamorphosis of the zebrafish, which occurs between 12-28 days post-fertilization, and is analogous to human fetal and neonatal development. Among the many changes that occur during zebrafish metamorphosis is the transformation of an embryonic/early larval pigment pattern into that of the adult, a process that depends on the recruitment of latent stem cells and is likely under hormonal control. As thyroid hormone (TH) is critical for amphibian metamorphosis as well as mammalian post-embryonic development.
Aim 1 will test roles for TH signaling in zebrafish somatic and pigment pattern metamorphosis. This will be accomplished using transgenic lines to block TH signals at specific times either throughout the fish or in specific cell lineages. To examine how global endocrine mediators effect local cellular processes of specification and morphogenesis, Aim 2 will test for interactions between TH signals and Wnt signals that are known to be critical for pigment cell 'development as well as stem cell self-renewal. These experiments will employ transgenic lines and other approaches to inhibit or stimulate these pathways and assay pathway activity and phenotypic outcomes. Finally, there may be many additional mediators of post-embryonic development, and to identify these, aim 3 will constitute a forward genetic screen for mutants that fail to undergo metamorphosis either entirely or have defects in the metamorphosis of specific traits and cell types. This screen will employ gene-breaking vectors and transposon-mediated insertional mutagenesis, allowing the efficient identification and analysis of affected loci. Together these efforts will provide significant new insights into the mechanisms of vertebrate post-embryonic development. *Vertebrates undergo extensive changes during postembryonic stages and many of these changes depend on the recruitment of differentiated progeny from self-renewing stem cell populations. Elucidating the genes, cell behaviors and hormonal mechanisms required for stem and progenitor cell renewal and differentiation is therefore important for understanding both human health and many disease syndromes and cancers.
|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|
|McMenamin, Sarah K; Minchin, James E N; Gordon, Tiffany N et al. (2013) Dwarfism and increased adiposity in the gh1 mutant zebrafish vizzini. Endocrinology 154:1476-87|