A large body of evidence in vertebrates shows that the development of the anterior trunk and the rest of the body are differentially regulated. Previous studies using mutants, knockouts, morpholinos and mRNA injection have provided very important information on the role of signaling and transcription factors in establishing the embryonic vertebrate body plan during the early gastrula stages. However, because alterations in the patterning of the early gastrula embryo cause such severe embryological defects, it has been difficult to study later stages when most of the body develops. Using transgenic lines containing heat-shock inducible cell autonomous regulators of signaling and transcription, together with a new transgenic line we developed that allows us to temporally and specifically label the mesodermal progenitors, we now have the ability to determine how the mesodermal progenitors are regulated by signaling and T-box transcription factors to progressively differentiate during somitogenesis, a process that is essential for forming a normal body and is conserved in all vertebrates. The studies described here take advantage of the ability in zebrafish to analyze the mesodermal progenitors at the single-cell level in living embryos, using cell transplants to study experimentally cell-autonomously perturbed cells within a normal background. This novel approach will allow us to examine cell behaviors that are obscured when all of the embryonic cells have alterations in signaling or transcription. Studies, particularly in mammals, show that the mesodermal progenitors are a stem-cell like population, which normally has a defined lifetime. With recent advances in the technology to produce transgenic lines, combined with the ability to study progenitors in living embryos using fluorescent reporters, zebrafish provides an excellent model system for understanding how vertebrate stem cells are regulated in vivo. As stem cells have great promise for the treatment of many diseases, the studies described here will provide valuable information about the signaling networks and transcription factors that control stem cell maintenance and tissue formation. Studies, particularly in mammals, show that the mesodermal progenitors are a stem-cell like population, which normally has a defined lifetime. With recent advances in the technology to produce transgenic lines, combined with the ability to study progenitors in living embryos using fluorescent reporters, zebrafish provides an excellent model system for understanding how vertebrate stem cells are regulated in vivo. As stem cells have great promise for the treatment of many diseases, the studies described here will provide valuable information about the signaling networks and transcription factors that control stem cell maintenance and tissue formation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM079203-04
Application #
8089543
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Haynes, Susan R
Project Start
2008-07-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$316,931
Indirect Cost
Name
University of Washington
Department
Biochemistry
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Kimelman, David (2016) Tales of Tails (and Trunks): Forming the Posterior Body in Vertebrate Embryos. Curr Top Dev Biol 116:517-36
Kimelman, David (2016) A novel cold-sensitive mutant of ntla reveals temporal roles of brachyury in zebrafish. Dev Dyn 245:874-80
Yoshimatsu, Takeshi; D'Orazi, Florence D; Gamlin, Clare R et al. (2016) Presynaptic partner selection during retinal circuit reassembly varies with timing of neuronal regeneration in vivo. Nat Commun 7:10590
Manning, Alyssa J; Kimelman, David (2015) Tbx16 and Msgn1 are required to establish directional cell migration of zebrafish mesodermal progenitors. Dev Biol 406:172-85
Bouldin, Cortney M; Manning, Alyssa J; Peng, Yu-Hsuan et al. (2015) Wnt signaling and tbx16 form a bistable switch to commit bipotential progenitors to mesoderm. Development 142:2499-507
Bouldin, Cortney M; Snelson, Corey D; Farr 3rd, Gist H et al. (2014) Restricted expression of cdc25a in the tailbud is essential for formation of the zebrafish posterior body. Genes Dev 28:384-95
Bouldin, Cortney M; Kimelman, David (2014) Dual fucci: a new transgenic line for studying the cell cycle from embryos to adults. Zebrafish 11:182-3
Suli, Arminda; Guler, Ali D; Raible, David W et al. (2014) A targeted gene expression system using the tryptophan repressor in zebrafish shows no silencing in subsequent generations. Development 141:1167-74
Bouldin, Cortney M; Kimelman, David (2014) Cdc25 and the importance of G2 control: insights from developmental biology. Cell Cycle 13:2165-71
Veldman, Matthew B; Zhao, Chengjian; Gomez, Gustavo A et al. (2013) Transdifferentiation of fast skeletal muscle into functional endothelium in vivo by transcription factor Etv2. PLoS Biol 11:e1001590

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