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      A novel source of arterial valve cells linked to bicuspid aortic valve without raphe in mice

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          Abstract

          Abnormalities of the arterial valve leaflets, predominantly bicuspid aortic valve, are the commonest congenital malformations. Although many studies have investigated the development of the arterial valves, it has been assumed that, as with the atrioventricular valves, endocardial to mesenchymal transition (EndMT) is the predominant mechanism. We show that arterial is distinctly different from atrioventricular valve formation. Whilst the four septal valve leaflets are dominated by NCC and EndMT-derived cells, the intercalated leaflets differentiate directly from Tnnt2-Cre+/Isl1+ progenitors in the outflow wall, via a Notch-Jag dependent mechanism. Further, when this novel group of progenitors are disrupted, development of the intercalated leaflets is disrupted, resulting in leaflet dysplasia and bicuspid valves without raphe, most commonly affecting the aortic valve. This study thus overturns the dogma that heart valves are formed principally by EndMT, identifies a new source of valve interstitial cells, and provides a novel mechanism for causation of bicuspid aortic valves without raphe.

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          Most cited references 60

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          Mutations in NOTCH1 cause aortic valve disease.

          Calcification of the aortic valve is the third leading cause of heart disease in adults. The incidence increases with age, and it is often associated with a bicuspid aortic valve present in 1-2% of the population. Despite the frequency, neither the mechanisms of valve calcification nor the developmental origin of a two, rather than three, leaflet aortic valve is known. Here, we show that mutations in the signalling and transcriptional regulator NOTCH1 cause a spectrum of developmental aortic valve anomalies and severe valve calcification in non-syndromic autosomal-dominant human pedigrees. Consistent with the valve calcification phenotype, Notch1 transcripts were most abundant in the developing aortic valve of mice, and Notch1 repressed the activity of Runx2, a central transcriptional regulator of osteoblast cell fate. The hairy-related family of transcriptional repressors (Hrt), which are activated by Notch1 signalling, physically interacted with Runx2 and repressed Runx2 transcriptional activity independent of histone deacetylase activity. These results suggest that NOTCH1 mutations cause an early developmental defect in the aortic valve and a later de-repression of calcium deposition that causes progressive aortic valve disease.
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            DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1.

            The DiGeorge/velocardiofacial syndrome (DGS/VCFS) is a relatively common human disorder, usually associated with deletions of chromosome 22q11. The genetic basis for the wide range of developmental anomalies in the heart, glands and facial structures has been elusive. We have investigated the potential role of one candidate gene, Tbx1, which encodes a transcription factor of the T-box family, by producing a null mutation in mice. We found that mice heterozygous for the mutation had a high incidence of cardiac outflow tract anomalies, thus modeling one of the major abnormalities of the human syndrome. Moreover, Tbx1-/- mice displayed a wide range of developmental anomalies encompassing almost all of the common DGS/VCFS features, including hypoplasia of the thymus and parathyroid glands, cardiac outflow tract abnormalities, abnormal facial structures, abnormal vertebrae and cleft palate. On the basis of this phenotype in mice, we propose that TBX1 in humans is a key gene in the etiology of DGS/VCFS.
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              Fate of the mammalian cardiac neural crest.

              A subpopulation of neural crest termed the cardiac neural crest is required in avian embryos to initiate reorganization of the outflow tract of the developing cardiovascular system. In mammalian embryos, it has not been previously experimentally possible to study the long-term fate of this population, although there is strong inference that a similar population exists and is perturbed in a number of genetic and teratogenic contexts. We have employed a two-component genetic system based on Cre/lox recombination to label indelibly the entire mouse neural crest population at the time of its formation, and to detect it at any time thereafter. Labeled cells are detected throughout gestation and in postnatal stages in major tissues that are known or predicted to be derived from neural crest. Labeling is highly specific and highly efficient. In the region of the heart, neural-crest-derived cells surround the pharyngeal arch arteries from the time of their formation and undergo an altered distribution coincident with the reorganization of these vessels. Labeled cells populate the aorticopulmonary septum and conotruncal cushions prior to and during overt septation of the outflow tract, and surround the thymus and thyroid as these organs form. Neural-crest-derived mesenchymal cells are abundantly distributed in midgestation (E9.5-12.5), and adult derivatives of the third, fourth and sixth pharyngeal arch arteries retain a substantial contribution of labeled cells. However, the population of neural-crest-derived cells that infiltrates the conotruncus and which surrounds the noncardiac pharyngeal organs is either overgrown or selectively eliminated as development proceeds, resulting for these tissues in a modest to marginal contribution in late fetal and postnatal life.
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                Author and article information

                Contributors
                Role: Reviewing Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                29 June 2018
                2018
                : 7
                Affiliations
                [1 ]deptInstitute of Genetic Medicine, Cardiovascular Research Centre Newcastle University Newcastle upon TyneUnited Kingdom
                [2 ]deptIntercellular Signalling in Cardiovascular Development and Disease Laboratory Centro Nacional de Investigaciones Cardiovasculares Carlos III MadridSpain
                [3 ]deptCentro de Investigación Biomédica en Red de Enfermedades Cardiovasculares Instituto de Salud Carlos III MadridSpain
                Max Planck Institute for Heart and Lung Research Germany
                Max Planck Institute for Heart and Lung Research Germany
                Article
                34110
                10.7554/eLife.34110
                6025960
                29956664
                © 2018, Eley et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                Product
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000274, British Heart Foundation;
                Award ID: RG/12/15/29935
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000274, British Heart Foundation;
                Award ID: PG/15/46/31589
                Award Recipient :
                Funded by: Ministerio de Ciencia, Innovación y Universidades of Spain;
                Award ID: CB16/11/00399 (Ciber Cardiovascular)
                Award Recipient :
                Funded by: Ministerio de Ciencia, Innovación y Universidades of Spain;
                Award ID: SAF2016-78370-R
                Award Recipient :
                Funded by: Ministerio de Ciencia, Innovación y Universidades of Spain;
                Award ID: RD16/0011/0021 (Red de Terapia Celular, TERCEL)
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Developmental Biology
                Custom metadata
                Identification of a novel source of progenitor cells that form arterial valve leaflets and that, when disrupted, can lead to bicuspid arterial valve, the most common human cardiac malformation.

                Life sciences

                bicuspid aortic valve, mouse, human, progenitor, second heart field, arterial valve

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