Connecting teratogen-induced congenital heart defects to neural crest cells and their effect on cardiac function

Abstract

Neural crest cells play many key roles in embryonic development, as demonstrated by the abnormalities that result from their specific absence or dysfunction. Unfortunately, these key cells are particularly sensitive to abnormalities in various intrinsic and extrinsic factors, such as genetic deletions or ethanol-exposure that lead to morbidity and mortality for organisms. This review discusses the role identified for a segment of neural crest in regulating the morphogenesis of the heart and associated great vessels. The paradox is that their derivatives constitute a small proportion of cells to the cardiovascular system. Findings supporting that these cells impact early cardiac function raises the interesting possibility that they indirectly control cardiovascular development at least partially through regulating function. Making connections between insults to the neural crest, cardiac function, and morphogenesis is more approachable with technological advances. Expanding our understanding of early functional consequences could be useful in improving diagnosis and testing therapies.

Keywords: cardiac; physiology; cardiogenesis; folic acid; neural crest cells; optical coherence tomography; ethanol; prenatal alcohol exposure; teratogen.

Figure 1. Potential consequences of NCC depletion

During normal development (left side) cardiac neural crest (CNC) cells from otic placode (Oto) to somite 3 (S3) travel from the CNC ventrolaterally to arrive at the circumpharyngeal ridge with a subset entering the branchial (pharyngeal) arches and a population enwrapping the aortic arch 3, 4, and 6 endothelial cells and contributing to remodeling of the aortic arch arteries as well as contributing to the media of these arteries as they differentiate into their asymmetric final structure. A few enter the outflow tract (OFT) and are responsible for the formation of the aortic-pulmonary septum. When the CNC are compromised (right side; e.g., undergo extensive cell death after ethanol treatment), few neural crest cells arrive at the circumpharygeal ridge, few populate the branchial arches, few contribute to the walls of the aortic arch arteries, and fewer than normal enter the heart for outflow tract (OFT) septation. With the failure of the interaction between neural crest and developing heart forming fields, the function of the heart becomes abnormal and could contribute to the development of CHDs. The figures at the top represent neural crest at stage 9–10, the stage ablations are usually conducted, and the bottom figures represent neural crest cell migrations that occur from stages 12 to 27. [Modified from Figure 11.4 (Kirby, 2007) by permission of Oxford University Press, USA. www.oup.com]

Figure 2. Juxtaposition of neural crest with heart forming mesoderm

Neural crest cell derivatives (NCC) are adjacent to heart forming mesoderm and in position to intercept and process signaling molecules from the foregut endoderm and/or endothelium/endocardium. AA=aortic arch, AS=aortic sac, End=endoderm, Ect=ectoderm, OFT= outflow tract, PA=pharyngeal (branchial) arch, Ph=pharynx. Adapted from (Kirby, 2007) and figures of an E9.5 mouse embryo section in (Kelly and Buckingham, 2002).

Figure 3. Connections

Ethanol exposure at gastrulation/neurulation stages causes CNCC abnormalities that lead to poor heart function. The resulting biomechanical forces fail to induce proper endocardial cushion development that is necessary for proper cardiac development including valve leaflet formation. Potential direct effects may contribute to abnormal functional parameters (boxes with ?). Direct effects of ethanol on cardiomyocytes and their precursors may directly affect abnormal heart function. Ethanol could also directly affect endocardial cells and other cell types that contribute to valve leaflet differentiation.