Congenital heart disease (CHD) is the most common birth defect. Among various CHDs, single ventricle phenotypes resulting from altered ventricular morphogenesis have the poorest clinical prognoses and include Tricuspid Atresia (TA; OMIM# 605067), Double Inlet Left Ventricle (DILV), Pulmonary Atresia (OMIM# 265150), and Hypoplastic Left Heart Syndrome (OMIM# 241550, 614435). The single ventricle heart presents with a series circuit such that systemic venous return to the right ventricle and pulmonary arteries combined with the flow from the pulmonary venous return into the left ventricle and out to the body is incompatible with survival. Currently, there is a poor understanding of the molecular mechanisms and cellular etiology causative of the many forms of single ventricle CHD. The Basic helix-loop-helix factor Hand2 is expressed within the myocardium of the second heart field (SHF), epicardium, cardiac neural crest cells, and endocardium. Hand2 deletion results in E10.5 embryonic lethality due to the decreased growth in SHF-derived cardiac structures. Mef2c-Cre deletion of Hand2 from SHF progenitor cells, results in TA/ DILV phenotypes. We have recently determined that the observed single ventricle phenotypes are a direct consequence of Hand2 function in the endocardium. The function of Hand2 within the endocardium has not been investigated. Our findings lead to a novel hypothesis that signaling from the developing endocardium is critical in determining the position of the ventricular septum, which may potentially explain the etiology of some single ventricle CHDs. We outline a strategy to both characterize Hand2 endocardial function, to identify the direct upstream endocardial signaling network for Hand2, and the Hand2-downstream transcriptional targets within the developing endocardium. Defining these endocardial signaling pathways and developmental programs regulated by Hand2 will shed light on the cell etiology of single ventricle phenotypes and on the molecular programs controlling ventricular septation, thus expanding the understanding of ventricular wall trabeculation, and septal morphogenesis.

Public Health Relevance

Hand2 loss-of-function within the endocardium results in Tricuspid Atresia and Double Inlet Left Ventricle phenotypes. Mutant hearts exhibit hypotrabeculation and defective septation. Results show that Hand2 sits within the Notch signaling pathway and plays an important role in modulating endocardial gene expression during embryogenesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL120920-04
Application #
9199584
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2013-12-15
Project End
2017-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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Firulli, Beth A; Milliar, Hannah; Toolan, Kevin P et al. (2017) Defective Hand1 phosphoregulation uncovers essential roles for Hand1 in limb morphogenesis. Development 144:2480-2489
Vincentz, Joshua W; Toolan, Kevin P; Zhang, Wenjun et al. (2017) Hand factor ablation causes defective left ventricular chamber development and compromised adult cardiac function. PLoS Genet 13:e1006922
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Li, Jingjing; Miao, Lianjie; Shieh, David et al. (2016) Single-Cell Lineage Tracing Reveals that Oriented Cell Division Contributes to Trabecular Morphogenesis and Regional Specification. Cell Rep 15:158-70
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Firulli, Beth A; Fuchs, Robyn K; Vincentz, Joshua W et al. (2014) Hand1 phosphoregulation within the distal arch neural crest is essential for craniofacial morphogenesis. Development 141:3050-61
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VanDusen, Nathan J; Casanovas, Jose; Vincentz, Joshua W et al. (2014) Hand2 is an essential regulator for two Notch-dependent functions within the embryonic endocardium. Cell Rep 9:2071-83

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