Krox20 defines a subpopulation of cardiac neural crest cells contributing to arterial valves and bicuspid aortic valve

Odelin, Gaëlle; Faure, Emilie; Coulpier, Fanny; Bonito, Maria Di; Bajolle, Fanny; Studer, Michèle; Avierinos, Jean-François; Charnay, Patrick; Topilko, Piotr; Zaffran, Stéphane

doi:10.1242/dev.151944

Cited by 46 publications

(64 citation statements)

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“…Arterial valve development is susceptible to imbalances in the ratio of mesodermal to NC cells in the leaflets (Odelin et al, ; Phillips et al, ). The Egr2 / Krox20 ‐expressing NC subpopulation emigrating from r5‐r6 (see Figure g,h) is particularly important for arterial valve development (Odelin et al, ). Thus, ectopic expression of Hoxb1 in NCCs from r5‐r6 may compromise their fate by interfering with the transcriptional readout of other transcription factors such as Krox20 (Desmazières, Charnay, & Gillardi‐Hebenstreit, ).…”

Section: Discussionmentioning

confidence: 99%

Ectopic expression of Hoxb1 induces cardiac and craniofacial malformations

Zaffran

Odelin

Stefanovic

et al. 2018

Genesis

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Members of the large family of Hox transcription factors are encoded by genes whose tightly regulated expression in development and in space within different embryonic tissues confer positional identity from the neck to the tips of the limbs. Many structures of the face, head, and heart develop from cell populations expressing few or no Hox genes. Hoxb1 is the member of its chromosomal cluster expressed in the most rostral domain during vertebrate development, but never by the multipotent neural crest cell population anterior to the cerebellum. We have developed a novel floxed transgenic mouse line, CAG-Hoxb1,-EGFP (CAG-Hoxb1), which upon recombination by Cre recombinase conditionally induces robust Hoxb1 and eGFP overexpression. When induced within the neural crest lineage, pups die at birth. A variable phenotype develops from E11.5 on, associating frontonasal hypoplasia/aplasia, micrognathia/agnathia, major ocular and forebrain anomalies, and cardiovascular malformations. Neural crest derivatives in the body appear unaffected. Transcription of effectors of developmental signaling pathways (Bmp, Shh, Vegfa) and transcription factors (Pax3, Sox9) is altered in mutants. These outcomes emphasize that repression of Hoxb1, along with other paralog group 1 and 2 Hox genes, is strictly necessary in anterior cephalic NC for craniofacial, visual, auditory, and cardiovascular development.

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Section: Discussionmentioning

confidence: 99%

Ectopic expression of Hoxb1 induces cardiac and craniofacial malformations

Zaffran

Odelin

Stefanovic

et al. 2018

Genesis

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“…Compound mutant mice were obtained by intercross Krox20+/− with Nos3+/− mice. The Krox20 Cre and Krox20 flox alleles and Tie2-cre, Wnt1-cre, −31/−23.5 Krox20/LacZ, and Gt(ROSA)26Sor tm9(CAG-tdTomato)Hze (Rosa tdTomato ) transgenic mice have been previously described [4].…”

Section: Micementioning

confidence: 99%

“…In humans, most BAVs result from fusion of either the right-coronary and left-coronary leaflets (R-L) or the right-coronary and non-coronary leaflets (R-N) [2]. BAV formation is considered to be an abnormal fusion of the aortic valve leaflets occurring during development [3,4]. Early valve development is a complex process involving the interplay of multiple cell lineages.…”

Section: Introductionmentioning

confidence: 99%

“…We have recently identified a sub-population of the neural crest that contribute to arterial valve development [4]. Neural crest cells are essential for positioning the OFT cushions and patterning the arterial valve leaflets [14].…”

Section: Introductionmentioning

confidence: 99%

“…We have recently shown that the transcription factor Krox20 (also called Egr2) plays an important role in aortic valve formation [4,12,22]. Indeed, Krox20−/− mice develop aortic insufficiency associated with partially penetrant R-N BAVs.…”

Section: Introductionmentioning

confidence: 99%

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Krox20 Regulates Endothelial Nitric Oxide Signaling in Aortic Valve Development and Disease

Odelin

Faure

Maurel-Zaffran

et al. 2019

JCDD

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Among the aortic valve diseases, the bicuspid aortic valve (BAV) occurs when the aortic valve has two leaflets (cusps), rather than three, and represents the most common form of congenital cardiac malformation, affecting 1–2% of the population. Despite recent advances, the etiology of BAV is poorly understood. We have recently shown that Krox20 is expressed in endothelial and cardiac neural crest derivatives that normally contribute to aortic valve development and that lack of Krox20 in these cells leads to aortic valve defects including partially penetrant BAV formation. Dysregulated expression of endothelial nitric oxide synthase (Nos3) is associated with BAV. To investigate the relationship between Krox20 and Nos3 during aortic valve development, we performed inter-genetic cross. While single heterozygous mice had normal valve formation, the compound Krox20+/−;Nos3+/− mice had BAV malformations displaying an in vivo genetic interaction between these genes for normal valve morphogenesis. Moreover, in vivo and in vitro experiments demonstrate that Krox20 directly binds to Nos3 proximal promoter to activate its expression. Our data suggests that Krox20 is a regulator of nitric oxide in endothelial-derived cells in the development of the aortic valve and concludes on the interaction of Krox20 and Nos3 in BAV formation.

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Development and evolution of the metazoan heart

Poelmann

Groot

2019

Developmental Dynamics

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The mechanisms of the evolution and development of the heart in metazoans are highlighted, starting with the evolutionary origin of the contractile cell, supposedly the precursor of cardiomyocytes. The last eukaryotic common ancestor is likely a combination of several cellular organisms containing their specific metabolic pathways and genetic signaling networks. During evolution, these tool kits diversified. Shared parts of these conserved tool kits act in the development and functioning of pumping hearts and open or closed circulations in such diverse species as arthropods, mollusks, and chordates. The genetic tool kits became more complex by gene duplications, addition of epigenetic modifications, influence of environmental factors, incorporation of viral genomes, cardiac changes necessitated by air‐breathing, and many others. We evaluate mechanisms involved in mollusks in the formation of three separate hearts and in arthropods in the formation of a tubular heart. A tubular heart is also present in embryonic stages of chordates, providing the septated four‐chambered heart, in birds and mammals passing through stages with first and second heart fields. The four‐chambered heart permits the formation of high‐pressure systemic and low‐pressure pulmonary circulation in birds and mammals, allowing for high metabolic rates and maintenance of body temperature. Crocodiles also have a (nearly) separated circulation, but their resting temperature conforms with the environment. We argue that endothermic ancestors lost the capacity to elevate their body temperature during evolution, resulting in ectothermic modern crocodilians. Finally, a clinically relevant paragraph reviews the occurrence of congenital cardiac malformations in humans as derailments of signaling pathways during embryonic development.

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Krox20 defines a subpopulation of cardiac neural crest cells contributing to arterial valves and bicuspid aortic valve

Cited by 46 publications

References 48 publications

Ectopic expression of Hoxb1 induces cardiac and craniofacial malformations

Ectopic expression of Hoxb1 induces cardiac and craniofacial malformations

Krox20 Regulates Endothelial Nitric Oxide Signaling in Aortic Valve Development and Disease

Development and evolution of the metazoan heart

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