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DiGeorge syndrome gene tbx1 functions through wnt11r to regulate heart morphology and function

Choudhry, Priya and Trede, Nikolaus S. (2013) DiGeorge syndrome gene tbx1 functions through wnt11r to regulate heart morphology and function. PLoS ONE, 8 (3). e58145. ISSN 1932-6203. PMCID PMC3606275. doi:10.1371/journal.pone.0058145.

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DiGeorge syndrome (DGS) is the most common microdeletion syndrome, and is characterized by congenital cardiac, craniofacial and immune system abnormalities. The cardiac defects in DGS patients include conotruncal and ventricular septal defects. Although the etiology of DGS is critically regulated by TBX1 gene, the molecular pathways underpinning TBX1's role in heart development are not fully understood. In this study, we characterized heart defects and downstream signaling in the zebrafish tbx1^(−/−) mutant, which has craniofacial and immune defects similar to DGS patients. We show that tbx1^(−/−) mutants have defective heart looping, morphology and function. Defective heart looping is accompanied by failure of cardiomyocytes to differentiate normally and failure to change shape from isotropic to anisotropic morphology in the outer curvatures of the heart. This is the first demonstration of tbx1's role in regulating heart looping, cardiomyocyte shape and differentiation, and may explain how Tbx1 regulates conotruncal development in humans. Next we elucidated tbx1's molecular signaling pathway guided by the cardiac phenotype of tbx1^(−/−) mutants. We show for the first time that wnt11r (wnt11 related), a member of the non-canonical Wnt pathway, and its downstream effector gene alcama (activated leukocyte cell adhesion molecule a) regulate heart looping and differentiation similarly to tbx1. Expression of both wnt11r and alcama are downregulated in tbx1^(−/−) mutants. In addition, both wnt11r^(−/−) mutants and alcama morphants have heart looping and differentiation defects similar to tbx1^(−/−) mutants. Strikingly, heart looping and differentiation in tbx1^(−/−) mutants can be partially rescued by ectopic expression of wnt11r or alcama, supporting a model whereby heart looping and differentiation are regulated by tbx1 in a linear pathway through wnt11r and alcama. This is the first study linking tbx1 and non-canonical Wnt signaling and extends our understanding of DGS and heart development.

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Additional Information:© 2013 Choudhry, Trede. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This work was supported in part by R01 HD047863-01 and by Award Number P30CA042014 from the National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have declared that no competing interests exist. The authors wish to thank Sarah Hutchinson, Tatjana Piotrowski and Joseph Yost for intellectual contributions. We wish to thank Tatjana Piotrowski for vgo^(tm208) (tbx1^(−/−)) mutant zebrafish and the Yost lab for Tg(cmlc2:EGFP) fish. The wnt11r ^(fh224/+) mutant line was obtained from the Moens lab TILLING project, which is supported by NIH grant HG002995. Several plasmids for ISH probes were kind gifts from Sheila Samson and Josh Wythe. Author Contributions: Wrote the manuscript: PC with editorial assistance from NST. Conceived and designed the experiments: PC NST. Performed the experiments: PC. Analyzed the data: PC NST. Contributed reagents/materials/analysis tools: PC NST.
Funding AgencyGrant Number
National Cancer IntsituteR01 HD047863-01
National Cancer InstituteP30CA042014
Issue or Number:3
PubMed Central ID:PMC3606275
Record Number:CaltechAUTHORS:20140416-132343837
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:44982
Deposited By: SWORD User
Deposited On:21 Apr 2014 23:47
Last Modified:10 Nov 2021 16:58

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