This proposal is focused on the tissue-specific role of the Pax3 transcription factor in the cardiac neural crest (CNC) lineage. CNC play an important role in cardiovascular development since derivatives contribute to the outflow tract (OFT) septum and remodeling pharyngeal arch arteries (AAs) that give rise to the great vessels exiting the heart. Mutations in Pax3 lead to persistent truncus arteriosus (PTA), interventricular septal defects (VSD) and abnormal pharyngeal AA remodeling. The type of cardiovascular defects present in these Pax3-deficient mice are similar to those observed in many cases of human congenital heart defects (CHDs). These heart defects also resemble cardiac anomalies observed in chick embryos when pre-migratory neural crest (NC)-containing neural folds are surgically ablated. Previous studies document that Splotch2H (Pax3-deficent) mutant embryos exhibit reduced pharyngeal arch and OFT CNC colonization caused by decreased NC progenitor expansion. Interestingly, genetic mutation of Pax3 does not entirely prevent CNC formation and migration. Our goals in this renewal application are to better define the role of Pax3 in the specification and function of CNC and finely titrate Pax3 levels in order to unambiguously determine the tissue-specific requirement of Pax3 in the CNC lineage using systemic null, hypomorphic and conditional mutant mouse models generated from our previous award. A hallmark of the Pax gene family is sensitivity to gene dosage, thus our finding that Pax7 (an orthologue of Pax3) can partially compensate for Pax3 reduction suggests Pax7 also plays a role in CNC morphogenesis. Preliminary data reveal that CNC-restricted deletion of Pax3 alone is not sufficient to cause OFT defects but that OFT defects manifest when there is a concomitant reduction in both Pax3 and Pax7 levels. Here, we propose that Pax3 plays two separable roles during CNC development. Initially a unique Pax3-mediated upstream NC progenitor specification function and a Pax3/7-mediated downstream function during subsequent CNC morphogenesis.
The specific aims of this proposal are to elucidate the requirement of Pax3 using single and combinatorial conditional Pax3 and Pax7 tissue-specific knockout approaches under temporal control in the mouse.
Aim 1 will examine whether Pax3/Pax7 compensation occurs in CNC lineage.
Aim 2 will examine whether pre-migratory CNC are pre-determined in the neural tube. Together these studies will advance the understanding of CNC function in heart development, and the mechanisms by which perturbations of CNC may contribute to congenital conotruncal defects.Narrative We will examine whether Pax3/Pax7 compensation occurs in CNC lineage. We will examine whether pre-migratory CNC are pre-determined in the neural tube. Together these studies will advance the understanding of CNC function in heart development, and the mechanisms by which perturbations of CNC may contribute to congenital conotruncal defects.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060714-12
Application #
7744016
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
1998-08-01
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
12
Fiscal Year
2010
Total Cost
$366,256
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
Rubart, Michael; Tao, Wen; Lu, Xiao-Long et al. (2017) Electrical coupling between ventricular myocytes and myofibroblasts in the infarcted mouse heart. Cardiovasc Res :
Zhou, Hong-Ming; Conway, Simon J (2016) Restricted Pax3 Deletion within the Neural Tube Results in Congenital Hydrocephalus. J Dev Biol 4:
Zhan, Hong; Aizawa, Kenichi; Sun, Junqing et al. (2016) Ataxia telangiectasia mutated in cardiac fibroblasts regulates doxorubicin-induced cardiotoxicity. Cardiovasc Res 110:85-95
Arima, Kazuhiko; Ohta, Shoichiro; Takagi, Atsushi et al. (2015) Periostin contributes to epidermal hyperplasia in psoriasis common to atopic dermatitis. Allergol Int 64:41-8
Simmons, Olga; Snider, Paige; Wang, Jain et al. (2015) Persistent Noggin arrests cardiomyocyte morphogenesis and results in early in utero lethality. Dev Dyn 244:457-67
Gehlhausen, Jeffrey R; Park, Su-Jung; Hickox, Ann E et al. (2015) A murine model of neurofibromatosis type 2 that accurately phenocopies human schwannoma formation. Hum Mol Genet 24:1-8
Jacob, Claire; Lötscher, Pirmin; Engler, Stefanie et al. (2014) HDAC1 and HDAC2 control the specification of neural crest cells into peripheral glia. J Neurosci 34:6112-22
Simmons, Olga; Bolanis, Esther M; Wang, Jian et al. (2014) In situ hybridization (both radioactive and nonradioactive) and spatiotemporal gene expression analysis. Methods Mol Biol 1194:225-44
Lajiness, Jacquelyn D; Snider, Paige; Wang, Jian et al. (2014) SHP-2 deletion in postmigratory neural crest cells results in impaired cardiac sympathetic innervation. Proc Natl Acad Sci U S A 111:E1374-82
Furtado, Milena B; Costa, Mauro W; Pranoto, Edward A et al. (2014) Cardiogenic genes expressed in cardiac fibroblasts contribute to heart development and repair. Circ Res 114:1422-34

Showing the most recent 10 out of 42 publications