The atrioventricular (AV) junction is the """"""""heart"""""""" of the embryonic heart, a central site where morphogenetic processes intersect to transform and align a tubular heart into a 4-chambered organ. Thus, it is not surprising that many human congenital heart defects can arguably be linked to AV junction formation and remodeling. For this revised, renewal application we continue to propose two aims directed at understanding the molecular mechanisms that regulate the assembly of multiple mesenchymal primordia into an AV valvuloseptal complex and its subsequent remodeling into a central fibrous body (or septum), AV septal valve leaflets and a fibrous continuity that anchors valves, aligns the ventricular inlet with their correct outlets and electrically insulates the atria from the ventricles.
These aims wil test hypotheses related to the formation (Aim 1) and remodeling (Aim 2) of the AV valvuloseptal complex. We focus on the function of two distinct matricellular proteins, CCN1/cry61 and periostin, whose expression patterns and null phenotypes indicate key signaling roles in AV morphogenesis and remodeling.
In Aim 1, we use CCN1 knockout mice with fully penetrant AV septal defects to test the hypothesis that CCN1 activates specific integrin signaling pathways in the AV progenitor cells that activate (phosphorylate) specific effector proteins associated with cell processes that drive formation, integration (fusion) and of the embryonic AV valvuloseptal complex. The effector proteins include hyaluronan synthetase2, caspase-3, and filamin-A which upon phosphorylation activate hyaluronan (HA) production, apoptosis and and filamin-A, an actin binding protein that regulates cytoskeletal functions.
In Aim 2, we test the hypothesis using genetic models and 3D culture assays that periostin - secreted by endocardial, epicardial and CD45 derived AV valvuloseptal progenitor cells - interacts with specific integrins to activate signaling complexes that activate filamin-A. Using gene silencing vectors or vectors expressing mutated FLNA that cannot be activated we will test the significance of FLNA activation on the differentiation and maturation of the AV valvuloseptal complex. Also, as a first step in understanding the functional significance of f the AV septal complex being derived from progenitor cells of different lineages , we will conditionally delete filamin-A, a downstream targe of periostin signaling from each lineage under the hypothesis that integration or interaction of mesenchymal subtypes is required for formation and remodeling of AV primordia. Unique aspects of this proposal are that we for the first time the whole of the AV complex, not just individual parts, and perform signaling studies that have rarely been extended to cardiac development.

Public Health Relevance

The proposed studies will identify the mechanisms by which matricellular proteins periostin and CCN1, based on their reciprocal expression patterns and null phenotypes, have key regulatory roles in the formation of the atrioventricular septal complex required for the AV junction remodelling into an adult heart phenotype.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Medical University of South Carolina
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Briggs, Laura E; Burns, Tara A; Lockhart, Marie M et al. (2016) Wnt/β-catenin and sonic hedgehog pathways interact in the regulation of the development of the dorsal mesenchymal protrusion. Dev Dyn 245:103-13
Rog-Zielinska, Eva A; Norris, Russell A; Kohl, Peter et al. (2016) The Living Scar--Cardiac Fibroblasts and the Injured Heart. Trends Mol Med 22:99-114
Sauls, Kimberly; Toomer, Katelynn; Williams, Katherine et al. (2015) Increased Infiltration of Extra-Cardiac Cells in Myxomatous Valve Disease. J Cardiovasc Dev Dis 2:200-213
Duval, Damien; Labbé, Pauline; Bureau, Léa et al. (2015) MVP-Associated Filamin A Mutations Affect FlnA-PTPN12 (PTP-PEST) Interactions. J Cardiovasc Dev Dis 2:233-247
Dina, Christian; Bouatia-Naji, Nabila; Tucker, Nathan et al. (2015) Genetic association analyses highlight biological pathways underlying mitral valve prolapse. Nat Genet 47:1206-11
Levine, Robert A; Hagége, Albert A; Judge, Daniel P et al. (2015) Mitral valve disease--morphology and mechanisms. Nat Rev Cardiol 12:689-710
Durst, Ronen; Sauls, Kimberly; Peal, David S et al. (2015) Mutations in DCHS1 cause mitral valve prolapse. Nature 525:109-13
Nagalakshmi, Vidya K; Lindner, Volkhard; Wessels, Andy et al. (2015) microRNA-dependent temporal gene expression in the ureteric bud epithelium during mammalian kidney development. Dev Dyn 244:444-56
Lockhart, Marie M; Boukens, Bastiaan J D; Phelps, Aimee L et al. (2014) Alk3 mediated Bmp signaling controls the contribution of epicardially derived cells to the tissues of the atrioventricular junction. Dev Biol 396:8-18
Twal, Waleed O; Klatt, Sandra C; Harikrishnan, Keerthi et al. (2014) Cellularized microcarriers as adhesive building blocks for fabrication of tubular tissue constructs. Ann Biomed Eng 42:1470-81

Showing the most recent 10 out of 92 publications