MEF2C regulates outflow tract alignment and transcriptional control of Tdgf1
| Autor: | Brian L. Black, Anabel Rojas, Ian S. Harris, David J. McCulley, William Schachterle, Russell A. Norris, Kimberly Sauls, Tanvi Sinha, Eric J. Jaehnig, Ralston M. Barnes |
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| Přispěvatelé: | National Institutes of Health (US), American Heart Association, American Lung Association |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Research Report Heart Septal Defects Ventricular Male Pathology Heart disease Mouse Transcription Genetic Organogenesis Transposition of Great Vessels Cripto Heart development Mice Morphogenesis MEF2C Tissue Distribution In Situ Hybridization education.field_of_study Membrane Glycoproteins MEF2 Transcription Factors Gene Expression Regulation Developmental Heart Anatomy Neoplasm Proteins medicine.anatomical_structure cardiovascular system Female MEF2 Heart Defects Congenital medicine.medical_specialty Tdgf1 Heart Ventricles Population Context (language use) Biology 03 medical and health sciences medicine Enhancers Animals Humans education Molecular Biology Epidermal Growth Factor Sequence Analysis RNA medicine.disease Disease Models Animal 030104 developmental biology Animals Newborn Ventricle Overriding aorta Gene Deletion Developmental Biology Enhancer |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname idUS. Depósito de Investigación de la Universidad de Sevilla |
| Popis: | Barnes, Ralston M. et al. Congenital heart defects are the most common birth defects in humans, and those that affect the proper alignment of the outflow tracts and septation of the ventricles are a highly significant cause of morbidity and mortality in infants. A late differentiating population of cardiac progenitors, referred to as the anterior second heart field (AHF), gives rise to the outflow tract and the majority of the right ventricle and provides an embryological context for understanding cardiac outflow tract alignment and membranous ventricular septal defects. However, the transcriptional pathways controlling AHF development and their roles in congenital heart defects remain incompletely elucidated. Here, we inactivated the gene encoding the transcription factor MEF2C in the AHF in mice. Loss of Mef2c function in the AHF results in a spectrum of outflow tract alignment defects ranging from overriding aorta to double-outlet right ventricle and dextro-transposition of the great arteries. We identify Tdgf1, which encodes a Nodal co-receptor (also known as Cripto), as a direct transcriptional target of MEF2C in the outflow tract via an AHF-restricted Tdgf1 enhancer. Importantly, both the MEF2C and TDGF1 genes are associated with congenital heart defects in humans. Thus, these studies establish a direct transcriptional pathway between the core cardiac transcription factor MEF2C and the human congenital heart disease gene TDGF1. Moreover, we found a range of outflow tract alignment defects resulting from a single genetic lesion, supporting the idea that AHF-derived outflow tract alignment defects may constitute an embryological spectrum rather than distinct anomalies. K.S. and R.A.N. performed work in a facility constructed with support from a National Institutes of Health (NIH) grant [C06 RR018823] and with support from NIH grants [GM103444 and HL127692] and an American Heart Association grant [15GRNT25080052]. This work was supported primarily by grants from the National Heart, Lung, and Blood Institute [R01 HL064658 and P01 HL089707 to B.L.B.]. |
| Databáze: | OpenAIRE |
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