Understanding heart development and congenital heart defects through developmental biology: A segmental approach

Abstract

The heart is the first organ to form and function during development. In the pregastrula chick embryo, cells contributing to the heart are found in the postero-lateral epiblast. During the pregastrula stages, interaction between the posterior epiblast and hypoblast is required for the anterior lateral plate mesoderm (ALM) to form, from which the heart will later develop. This tissue interaction is replaced by an Activin-like signal in culture. During gastrulation, the ALM is committed to the heart lineage by endoderm-secreted BMP and subsequently differentiates into cardiomyocyte. The right and left precardiac mesoderms migrate toward the ventral midline to form the beating primitive heart tube. Then, the heart tube generates a right-side bend, and the d-loop and presumptive heart segments begin to appear segmentally: outflow tract (OT), right ventricle, left ventricle, atrioventricular (AV) canal, atrium and sinus venosus. T-box transcription factors are involved in the formation of the heart segments: Tbx5 identifies the left ventricle and Tbx20 the right ventricle. After the formation of the heart segments, endothelial cells in the OT and AV regions transform into mesenchyme and generate valvuloseptal endocardial cushion tissue. This phenomenon is called endocardial EMT (epithelial-mesenchymal transformation) and is regulated mainly by BMP and TGFbeta. Finally, heart septa that have developed in the OT, ventricle, AV canal and atrium come into alignment and fuse, resulting in the completion of the four-chambered heart. Altered development seen in the cardiogenetic process is involved in the pathogenesis of congenital heart defects. Therefore, understanding the molecular nature regulating the 'nodal point' during heart development is important in order to understand the etiology of congenital heart defects, as well as normal heart development.

Impairment of endothelial‐mesenchymal transformation during atrioventricular cushion formation in Tmem100 null embryos

“…Numerous growth factors, transmembrane receptors, and intracellular signaling molecules are implicated in the regulation of cushion formation (Armstrong and Bischoff, 2004;Sakabe et al, 2005;Lin et al, 2012;von Gise and Pu, 2012). Among those are transforming growth factor beta (TGFb) and bone morphogenetic protein (BMP), which act as myocardium-derived signals to induce EndMT of endocardial cells (Yamagishi et al, 1999;Camenisch et al, 2002;Sugi et al, 2004;Ma et al, 2005).…”

“…Remodeling of the primitive heart tube into mature fourchambered heart requires the formation of endocardial cushion tissue in the atrioventricular canal (AVC) and outflow tract (OFT) (Markwald et al, 1975;Armstrong and Bischoff, 2004;Sakabe et al, 2005;Combs and Yutzey, 2009a;Lin et al, 2012;von Gise and Pu, 2012). Endocardial cells in these specific regions perform a sequence of phenotypic changes called endothelialmesenchymal transformation (EndMT), including delamination and repopulation into underlying extracellular matrix to form the cushion tissues.…”

Ectopic retinoic acid signaling affects outflow tract cushion development through suppression of the myocardial Tbx2-Tgfβ2 pathway

“…During OFT development, some of the endothelial cells lining the OFT region are activated by signaling molecules secreted from the adjacent myocardium to undergo the endothelial-mesenchymal transformation (EMT). Subsequently, the transformed mesenchymal cells invade the matrix-rich cardiac jelly to form conotruncal endocardial cushion tissue (Markwald et al, 1975;Sakabe et al, 2005), and then neural crest cells also migrate through the pharyngeal arches to fill the OFT cushions (Hutson and Kirby, 2007). Abnormal EMT or neural crest migration causes several congenital heart defects, such as transposition of the great arteries (TGA), double outlet right ventricle (DORV), and persistent truncus arteriosus (PTA).…”

Roles of TGFβ and BMP during valvulo–septal endocardial cushion formation

“…As development proceeds, the aorticopulmonary, outflow, interventricular, AV, and primary atrial septa align and fuse, resulting in the formation of a four-chambered heart. Consequently, thus, abnormal development of endocardial cushion tissues causes various heart malformations, such as transposition of the great arteries and AV septum defect (Sakabe et al 2005).…”