Atrial septation is a critical step in separating the systemic and pulmonary circulations in tetrapods and atrial septal defects are among the most common forms of human congenital heart disease (CHD). The objective of this project is to investigate the cellular and molecular mechanisms required for atrial septation and atrial septal progenitor cell specification. The canonical view of atrial septation is based on intracardiac morphogenetic events. However, recent work in our laboratory and others has engendered a novel paradigm for atrial septation, based on contributions from the second heart field (Mommersteeg et al., 2006;Snarr et al., 2007b;Goddeeris et al., 2008). We have identified a subset of cardiac progenitor cells specific for the atrial septum. Hedgehog signaling in the posterior second heart field marks atrial septal progenitors. These findings imply that atrial septum vs. non-septum cell fate is distinguished at the level of progenitor cell specification rather than by positional information acquired subsequently within the developing atrium. The molecular mechanisms by which these newly characterized progenitor cells are specified and generate the atrial septum are currently unknown. Here, we propose an integrative approach using both forward and reverse genetics to build a molecular pathway required for atrial septation and investigate the specification of atrial septal progenitors.
Our specific aims are to (1) Analyze the specification, proliferation, and survival of atrial septal progenitors in wild-type and Hedgehog signaling mutant embryos;(2) Analyze atrial septal progenitors and Hh signaling in cac2 mutant mice;and (3) Identify the molecular basis of cac2, a novel gene required for atrial septation. A greater understanding of the molecular basis of atrial septal progenitor cell specification and function will be delivered at the end of the granting period. This work will contribute to an ongoing paradigm shift in our understanding of the ontogeny of cardiac septal defects.

Public Health Relevance

Atrial septation is a critical step in separating the systemic and pulmonary circulations in tetrapods and atrial septal defects are among the most common forms of human congenital heart disease. The objective of this project is to gain a better understanding of atrial septal progenitor cell specification and function. The long- term goal of this work is to understand the ontogeny of atrial septal defects.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL092153-04
Application #
8309462
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2009-09-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$380,778
Indirect Cost
$133,278
Name
University of Chicago
Department
Pediatrics
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Burnicka-Turek, Ozanna; Steimle, Jeffrey D; Huang, Wenhui et al. (2016) Cilia gene mutations cause atrioventricular septal defects by multiple mechanisms. Hum Mol Genet 25:3011-3028
Priest, James R; Osoegawa, Kazutoyo; Mohammed, Nebil et al. (2016) De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects. PLoS Genet 12:e1005963
Waldron, Lauren; Steimle, Jeffrey D; Greco, Todd M et al. (2016) The Cardiac TBX5 Interactome Reveals a Chromatin Remodeling Network Essential for Cardiac Septation. Dev Cell 36:262-75
Hoffmann, Andrew D; Yang, Xinan Holly; Burnicka-Turek, Ozanna et al. (2014) Foxf genes integrate tbx5 and hedgehog pathways in the second heart field for cardiac septation. PLoS Genet 10:e1004604
Xie, Linglin; Hoffmann, Andrew D; Burnicka-Turek, Ozanna et al. (2012) Tbx5-hedgehog molecular networks are essential in the second heart field for atrial septation. Dev Cell 23:280-91
Smemo, Scott; Campos, Luciene C; Moskowitz, Ivan P et al. (2012) Regulatory variation in a TBX5 enhancer leads to isolated congenital heart disease. Hum Mol Genet 21:3255-63
Kim, Eun Young; Chen, Li; Ma, Yanlin et al. (2012) Enhanced desumoylation in murine hearts by overexpressed SENP2 leads to congenital heart defects and cardiac dysfunction. J Mol Cell Cardiol 52:638-49
Arnolds, David E; Moskowitz, Ivan P (2011) Inducible recombination in the cardiac conduction system of minK: CreERT² BAC transgenic mice. Genesis 49:878-84
Friedland-Little, Joshua M; Hoffmann, Andrew D; Ocbina, Polloneal Jymmiel R et al. (2011) A novel murine allele of Intraflagellar Transport Protein 172 causes a syndrome including VACTERL-like features with hydrocephalus. Hum Mol Genet 20:3725-37
Moskowitz, Ivan P; Wang, Jun; Peterson, Michael A et al. (2011) Transcription factor genes Smad4 and Gata4 cooperatively regulate cardiac valve development. [corrected] Proc Natl Acad Sci U S A 108:4006-11

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