Organs in the vertebrate body are usually formed by large numbers of cells that are derived from multiple embryonic tissues and that have diverse physiological and structural functions. This complexity makes it difficult to unravel the networks that control the molecular mechanisms of organogenesis. In contrast, Kupffer's Vesicle (KV) is a'^highly organized embryonic structurethat is comprised of approximately four dozen cells. These cells are derived from Dorsal Forerunner Cells (DFCs) that migrate during gastrulation and then ingress into the tailbud to form the KV. Although the KV was described in 1868 and is highly conserved in teleosts, until our studies the function of KV was unknown. We found that KV epithelial lining has motile cilia that project into the lumen of KV and generate right-left asymmetric fluid flow. Using mutants, morpholino injections and laser ablations, we have discovered the function of the DFCs and KV: regulation of LR patterning in the brain, heart and gut primordia. We have shown that two T-box transcription factor genes, no tail (ntl) and spadetail (spt), have multiple roles in KV cilia gene expression, organogenesis, patterning and function. Some of these roles are distinct, and some are overlapping, suggesting that there are multiple cohorts of genes controlled by ntl, spt or combinatorial interactions between ntl, spt and other pathways. Our preliminary results indicate that the transcription factor genes rfx2 and hfh4 intersect with these T-box-dependent pathways; morphants of these genes do not alter KV formation, but alter the ability of cilia to function properly. The goal of this project is to elucidate the complex regulatory interactions, based on four transcription factor genes, ntl, spt, rfx2 and hfh4, that coordinate the formation, ciliagenesis and function of this simple but essential embryonic organ.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
1P01HD048886-01A2
Application #
7193071
Study Section
Pediatrics Subcommittee (CHHD)
Project Start
2006-12-01
Project End
2011-11-30
Budget Start
2007-03-25
Budget End
2008-02-29
Support Year
1
Fiscal Year
2007
Total Cost
$168,285
Indirect Cost
Name
University of Utah
Department
Type
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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Yabe, Taijiro; Hoshijima, Kazuyuki; Yamamoto, Takashi et al. (2016) Quadruple zebrafish mutant reveals different roles of Mesp genes in somite segmentation between mouse and zebrafish. Development 143:2842-52
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Wythe, Joshua D; Jurynec, Michael J; Urness, Lisa D et al. (2011) Hadp1, a newly identified pleckstrin homology domain protein, is required for cardiac contractility in zebrafish. Dis Model Mech 4:607-21

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