Heart formation involves a complex series of events in which cells from numerous sources, including the primary and secondary heart fields, neural crest, epicardium and endocardium must interact in specialized ways to form the complex structures of the heart, such as the ventricular chambers, valves and coronary arteries. Our laboratory has discovered four families of basic helix-loop-helix (bHLH) transcription factors (Hands, Hrts, MyoR/capsulin and Twist) that play key roles in multiple steps of cardiac growth and development. The overall goals of this project are to use these bHLH genes as entry points into the developmental circuits that control heart formation and function. We intend to continue to define the roles of bHLH genes in cardiovascular development through lineage analyses and loss-of-function studies in vivo and mechanistic studies in vitro. We will also extend recent observations implicating several cardiovascular bHLH genes in myocardial remodeling, repair, and neovascularization in response to injury. As a complement to our primary focus on mammalian cardiovascular development, we have generated transgenic flies that express green fluorescent protein (GFP) under control of cardiac-specific regulatory elements of the Drosophila Hand gene, which, like the mammalian Hand genes, serves as an early marker of cardiac lineages. These flies have enabled us to undertake an unbiased search for genes that regulate cardial cell specification, differentiation, patterning, growth, morphogenesis and contractility of the heart. The cloning of these mutant genes and eventual elucidation of their functions should provide new insights into the fundamental circuitry of cardiac development and reveal candidate genes for further exploration in mammalian heart development and congenital heart disease.
Abnormalities in heart formation give rise to congenital heart disease, the most common form of human birth defects. Our laboratory has discovered proteins that play key roles in cardiac development and will use these proteins to elucidate the developmental events that control normal heart formation and function. Understanding the function of these proteins will reveal new insights into the fundamental circuitry of cardiac development and provide approaches to combat congenital heart disease.
|Liu, Ning; Garry, Glynnis A; Li, Stephen et al. (2017) A Twist2-dependent progenitor cell contributes to adult skeletal muscle. Nat Cell Biol 19:202-213|
|Baskin, Kedryn K; Makarewich, Catherine A; DeLeon, Susan M et al. (2017) MED12 regulates a transcriptional network of calcium-handling genes in the heart. JCI Insight 2:|
|Kyrychenko, Viktoriia; Kyrychenko, Sergii; Tiburcy, Malte et al. (2017) Functional correction of dystrophin actin binding domain mutations by genome editing. JCI Insight 2:|
|Zhou, Huanyu; Morales, Maria Gabriela; Hashimoto, Hisayuki et al. (2017) ZNF281 enhances cardiac reprogramming by modulating cardiac and inflammatory gene expression. Genes Dev 31:1770-1783|
|Abad, Maria; Hashimoto, Hisayuki; Zhou, Huanyu et al. (2017) Notch Inhibition Enhances Cardiac Reprogramming by Increasing MEF2C Transcriptional Activity. Stem Cell Reports 8:548-560|
|Moon, Jesung; Zhou, Huanyu; Zhang, Li-Shu et al. (2017) Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist. Proc Natl Acad Sci U S A 114:1649-1654|
|Amoasii, Leonela; Long, Chengzu; Li, Hui et al. (2017) Single-cut genome editing restores dystrophin expression in a new mouse model of muscular dystrophy. Sci Transl Med 9:|
|Ramirez-Martinez, Andres; Cenik, Bercin Kutluk; Bezprozvannaya, Svetlana et al. (2017) KLHL41 stabilizes skeletal muscle sarcomeres by nonproteolytic ubiquitination. Elife 6:|
|Polster, Alexander; Nelson, Benjamin R; Olson, Eric N et al. (2016) Stac3 has a direct role in skeletal muscle-type excitation-contraction coupling that is disrupted by a myopathy-causing mutation. Proc Natl Acad Sci U S A 113:10986-91|
|Millay, Douglas P; Gamage, Dilani G; Quinn, Malgorzata E et al. (2016) Structure-function analysis of myomaker domains required for myoblast fusion. Proc Natl Acad Sci U S A 113:2116-21|
Showing the most recent 10 out of 90 publications