Strong conservation of heart formation along the left-right (LR) axis among vertebrates suggests that common developmental mechanisms and genetic pathways exist for left-right development. However, despite abundant evidence supporting a role for nodal monocilia in the establishment of LR asymmetry, little is known about formation of the late gastrula node. In zebrafish, the node equivalent is Kupffer's vesicle (KV). KV contains monocilia, generates asymmetric fluid flow, and is necessary for left-sided expression of downstream laterality genes. Because KV is easily visualized and experimentally manipulated in zebrafish, the candidate will use this model system to better understand KV formation and its role in LR development. From preliminary studies, he has discovered that syndecan-2, a single-pass transmembrane heparan sulfate proteoglycan, is required for normal LR development and plays a cell-autonomous role in KV formation. Morpholino knockdown of syndecan-2 causes reversal of heart and gut looping and leads to misshapen KV with fewer and shorter cilia. Based on these observations, the candidate proposes to further define the role of syndecan-2 in KV and cilia formation/function and explore the necessary molecular interactions of syndecan-2 during the process of KV development. Through this study, genetic and molecular mechanisms that regulate cardiac LR development will be discovered and one day used to improve detection and treatment of congenital heart disease in children.

Public Health Relevance

Abnormalities in left-right development often lead to complex congenital heart defects with significant associated morbidity and mortality, but little is known about the molecular anomalies that cause these defects. Understanding the mechanisms that regulate left-right development in model vertebrate systems will advance our ability to understand, detect, and treat human cardiovascular malformations.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HD062638-04
Application #
8440330
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Javois, Lorette Claire
Project Start
2010-02-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
4
Fiscal Year
2013
Total Cost
$137,065
Indirect Cost
$10,065
Name
University of Utah
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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Arrington, Cammon B; Peterson, Annita G; Yost, H Joseph (2013) Sdc2 and Tbx16 regulate Fgf2-dependent epithelial cell morphogenesis in the ciliated organ of asymmetry. Development 140:4102-9