Bicuspid aortic valve formation:  Nos3  mutation leads to abnormal lineage patterning of neural crest cells and the second heart field

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ABSTRACT

The bicuspid aortic valve (BAV), a valve with two instead of three aortic leaflets, belongs to the most prevalent congenital heart diseases in the world, occurring in 0.5-2% of the general population. We aimed to understand how changes in early cellular contributions result in BAV formation and impact cardiovascular outflow tract development. Detailed 3D reconstructions, immunohistochemistry and morphometrics determined that, during valvulogenesis, the non-coronary leaflet separates from the parietal outflow tract cushion instead of originating from an intercalated cushion. Nos3 ^−/− mice develop a BAV without a raphe as a result of incomplete separation of the parietal outflow tract cushion into the right and non-coronary leaflet. Genetic lineage tracing of endothelial, second heart field and neural crest cells revealed altered deposition of neural crest cells and second heart field cells within the parietal outflow tract cushion of Nos3 ^−/− embryos. The abnormal cell lineage distributions also affected the positioning of the aortic and pulmonary valves at the orifice level. The results demonstrate that the development of the right and non-coronary leaflets are closely related. A small deviation in the distribution of neural crest and second heart field populations affects normal valve formation and results in the predominant right-non-type BAV in Nos3 ^−/− mice.

Abstract

Summary: The endothelial Nos3 mutation impacts neural-crest and second-heart-field lineage patterning within the aortic valve, which affects outflow-tract formation, as well as aortopulmonary angulation.

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Most cited references 47

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Some new, simple and efficient stereological methods and their use in pathological research and diagnosis.

H J Gundersen, T Bendtsen, L Korbo … (1988)

Stereology is a set of simple and efficient methods for quantitation of three-dimensional microscopic structures which is specifically tuned to provide reliable data from sections. Within the last few years, a number of new methods has been developed which are of special interest to pathologists. Methods for estimating the volume, surface area and length of any structure are described in this review. The principles on which stereology is based and the necessary sampling procedures are described and illustrated with examples. The necessary equipment, the measurements, and the calculations are invariably simple and easy.

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A classification system for the bicuspid aortic valve from 304 surgical specimens.

Hans-H. Sievers, Claudia Schmidtke (2007)

In general, classification of a disease has proven to be advantageous for disease management. This may also be valid for the bicuspid aortic valve, because the term "bicuspid aortic valve" stands for a common congenital aortic valve malformation with heterogeneous morphologic phenotypes and function resulting in different treatment strategies. We attempted to establish a classification system based on a 5-year data collection of surgical specimens. Between 1999 and 2003 a precise description of valve pathology was obtained from operative reports of 304 patients with a diseased bicuspid aortic valve. Several different characteristics of bicuspid aortic valves were tested to generate a pithy and easily applicable classification system. Three characteristics for a systematic classification were found appropriate: (1) number of raphes, (2) spatial position of cusps or raphes, and (3) functional status of the valve. The first characteristic was found to be the most significant and therefore termed "type." Three major types were identified: type 0 (no raphe), type 1 (one raphe), and type 2 (two raphes), followed by two supplementary characteristics, spatial position and function. These characteristics served to classify and codify the bicuspid aortic valves into three categories. Most frequently, a bicuspid aortic valve with one raphe was identified (type 1, n = 269). This raphe was positioned between the left (L) and right (R) coronary sinuses in 216 (type 1, L/R) with a hemodynamic predominant stenosis (S) in 119 (type 1, L/R, S). Only 21 patients had a "purely" bicuspid aortic valve with no raphe (type 0). A classification system for the bicuspid aortic valve with one major category ("type") and two supplementary categories is presented. This classification, even if used in the major category (type) alone, might be advantageous to better define bicuspid aortic valve disease, facilitate scientific communication, and improve treatment.

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Fate of the mammalian cardiac neural crest.

X Jiang, D Rowitch, P Soriano … (2000)

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

Journal

Journal ID (nlm-ta): Dis Model Mech

Journal ID (iso-abbrev): Dis Model Mech

Journal ID (publisher-id): DMM

Journal ID (hwp): dmm

Title: Disease Models & Mechanisms

Publisher: The Company of Biologists Ltd

ISSN (Print): 1754-8403

ISSN (Electronic): 1754-8411

Publication date (Print): 1 October 2018

Publication date (Electronic): 19 October 2018

Publication date PMC-release: 19 October 2018

Volume: 11

Issue: 10

Electronic Location Identifier: dmm034637

Affiliations

[1 ]Dept. Anatomy and Embryology, Leiden University Medical Center , PO Box 9600, 2300 RC Leiden, The Netherlands

[2 ]Dept. Cardiology, Leiden University Medical Center , PO Box 9600, 2300 RC Leiden, The Netherlands

[3 ]Dept. Physiology and Pharmacology, Schulich Medicine & Dentistry, Western University , London, ON N6A 5C1, Canada

[4 ]Dept. Molecular Cell Biology, Leiden University Medical Center , PO Box 9600, 2300 RC Leiden, The Netherlands

Author notes

[*]

These authors contributed equally to this work

[‡ ]Author for correspondence ( m.c.deruiter@ 123456lumc.nl )

Author information

Joshua C. Peterson http://orcid.org/0000-0001-5792-2725

Qingping Feng http://orcid.org/0000-0001-9739-2765

Marie-José T. H. Goumans http://orcid.org/0000-0001-9344-6746

Marco C. DeRuiter http://orcid.org/0000-0002-0528-7464

Article

Publisher ID: DMM034637

DOI: 10.1242/dmm.034637

PMC ID: 6215433

PubMed ID: 30242109

SO-VID: 03acbbdc-05b8-4de1-9d40-8aa0ee032897

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

History

Date received : 22 March 2018

Date accepted : 5 September 2018

Funding

Funded by: Hartstichting, http://dx.doi.org/10.13039/501100002996;

Award ID: 31190BAV

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Bicuspid aortic valve formation: Nos3 mutation leads to abnormal lineage patterning of neural crest cells and the second heart field

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Most cited references 47

Some new, simple and efficient stereological methods and their use in pathological research and diagnosis.

A classification system for the bicuspid aortic valve from 304 surgical specimens.

Fate of the mammalian cardiac neural crest.

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Cited by 19

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