Publications by authors named "Corinne Maurel-Zaffran"

13 Publications

  • Page 1 of 1

-dependent coordination of mouse cardiac progenitor cell patterning and differentiation.

Elife 2020 08 17;9. Epub 2020 Aug 17.

Aix Marseille Univ, INSERM, Marseille Medical Genetics, Marseille, France.

Perturbation of addition of second heart field (SHF) cardiac progenitor cells to the poles of the heart tube results in congenital heart defects (CHD). The transcriptional programs and upstream regulatory events operating in different subpopulations of the SHF remain unclear. Here, we profile the transcriptome and chromatin accessibility of anterior and posterior SHF sub-populations at genome-wide levels and demonstrate that Hoxb1 negatively regulates differentiation in the posterior SHF. Spatial mis-expression of in the anterior SHF results in hypoplastic right ventricle. Activation of in embryonic stem cells arrests cardiac differentiation, whereas -deficient mouse embryos display premature cardiac differentiation. Moreover, ectopic differentiation in the posterior SHF of embryos lacking both and its paralog results in atrioventricular septal defects. Our results show that Hoxb1 plays a key role in patterning cardiac progenitor cells that contribute to both cardiac poles and provide new insights into the pathogenesis of CHD.
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http://dx.doi.org/10.7554/eLife.55124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462617PMC
August 2020

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

J Cardiovasc Dev Dis 2019 Nov 2;6(4). Epub 2019 Nov 2.

Aix Marseille University, INSERM, Marseille Medical Genetics, U1251, 13005 Marseille, France.

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 is expressed in endothelial and cardiac neural crest derivatives that normally contribute to aortic valve development and that lack of 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 and during aortic valve development, we performed inter-genetic cross. While single heterozygous mice had normal valve formation, the compound ; 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 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 and in BAV formation.
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http://dx.doi.org/10.3390/jcdd6040039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955692PMC
November 2019

The Generic Facet of Hox Protein Function.

Trends Genet 2018 12 18;34(12):941-953. Epub 2018 Sep 18.

Aix Marseille Univ, CNRS, IBDM, Marseille, France; http://www.ibdm.univ-mrs.fr/equipe/mechanisms-of-gene-regulation-by-transcription-factors/. Electronic address:

Hox transcription factors are essential to promote morphological diversification of the animal body. A substantial number of studies have focused on how Hox proteins reach functional specificity, an issue that arises from the fact that these transcription factors control distinct developmental functions despite sharing similar molecular properties. In this review, we highlight that, besides specific functions, for which these transcription factors are renowned, Hox proteins also often have nonspecific functions. We next discuss some emerging principles of these generic functions and how they relate to specific functions and explore our current grasp of the underlying molecular mechanisms.
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http://dx.doi.org/10.1016/j.tig.2018.08.006DOI Listing
December 2018

Hox functional diversity: Novel insights from flexible motif folding and plastic protein interaction.

Bioessays 2017 04 16;39(4). Epub 2017 Jan 16.

Aix-Marseille-Université, CNRS UMR 7288, case 907, IBDM, Marseille, France.

How the formidable diversity of forms emerges from developmental and evolutionary processes is one of the most fascinating questions in biology. The homeodomain-containing Hox proteins were recognized early on as major actors in diversifying animal body plans. The molecular mechanisms underlying how this transcription factor family controls a large array of context- and cell-specific biological functions is, however, still poorly understood. Clues to functional diversity have emerged from studies exploring how Hox protein activity is controlled through interactions with PBC class proteins, also evolutionary conserved HD-containing proteins. Recent structural data and molecular dynamic simulations add further mechanistic insights into Hox protein mode of action, suggesting that flexible folding of protein motifs allows for plastic protein interaction. As we discuss in this review, these findings define a novel type of Hox-PBC interaction, weak and dynamic instead of strong and static, hence providing novel clues to understanding Hox transcriptional specificity and diversity.
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http://dx.doi.org/10.1002/bies.201600246DOI Listing
April 2017

A survey of conservation of sea spider and Drosophila Hox protein activities.

Mech Dev 2015 Nov 1;138 Pt 2:73-86. Epub 2015 Aug 1.

Aix Marseille Université, CNRS, IBDM, UMR 7288, Campus de Luminy, Marseille, cedex 09 13288, France.

Hox proteins have well-established functions in development and evolution, controlling the final morphology of bilaterian animals. The common phylogenetic origin of Hox proteins and the associated evolutionary diversification of protein sequences provide a unique framework to explore the relationship between changes in protein sequence and function. In this study, we aimed at questioning how sequence variation within arthropod Hox proteins influences function. This was achieved by exploring the functional impact of sequence conservation/divergence of the Hox genes, labial, Sex comb reduced, Deformed, Ultrabithorax and abdominalA from two distant arthropods, the sea spider and the well-studied Drosophila. Results highlight a correlation between sequence conservation within the homeodomain and the degree of functional conservation, and identify a novel functional domain in the Labial protein.
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http://dx.doi.org/10.1016/j.mod.2015.07.010DOI Listing
November 2015

Cellular and molecular insights into Hox protein action.

Development 2015 Apr;142(7):1212-27

Aix Marseille Université, CNRS, IBDM, UMR 7288, Marseille 13288, Cedex 09, France

Hox genes encode homeodomain transcription factors that control morphogenesis and have established functions in development and evolution. Hox proteins have remained enigmatic with regard to the molecular mechanisms that endow them with specific and diverse functions, and to the cellular functions that they control. Here, we review recent examples of Hox-controlled cellular functions that highlight their versatile and highly context-dependent activity. This provides the setting to discuss how Hox proteins control morphogenesis and organogenesis. We then summarise the molecular modalities underlying Hox protein function, in particular in light of current models of transcription factor function. Finally, we discuss how functional divergence between Hox proteins might be achieved to give rise to the many facets of their action.
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http://dx.doi.org/10.1242/dev.109785DOI Listing
April 2015

A flexible extension of the Drosophila ultrabithorax homeodomain defines a novel Hox/PBC interaction mode.

Structure 2015 Feb;23(2):270-9

Centre National de la Recherche Scientifique, Aix-Marseille Université, CNRS UMR 7288, IBDM, Parc Scientifique de Luminy, Case 907, 13288 Marseille Cedex 09, France. Electronic address:

The patterning function of Hox proteins relies on assembling protein complexes with PBC proteins, which often involves a protein motif found in most Hox proteins, the so-called Hexapeptide (HX). Hox/PBC complexes likely gained functional diversity by acquiring additional modes of interaction. Here, we structurally characterize the first HX alternative interaction mode based on the paralogue-specific UbdA motif and further functionally validate structure-based predictions. The UbdA motif folds as a flexible extension of the homeodomain recognition helix and defines Hox/PBC contacts that occur, compared with those mediated by the HX motif, on the opposing side of the DNA double helix. This provides a new molecular facet to Hox/PBC complex assembly and suggests possible mechanisms for the diversification of Hox protein function.
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http://dx.doi.org/10.1016/j.str.2014.12.011DOI Listing
February 2015

Loss of Krox20 results in aortic valve regurgitation and impaired transcriptional activation of fibrillar collagen genes.

Cardiovasc Res 2014 Dec 24;104(3):443-55. Epub 2014 Oct 24.

Aix Marseille Université, GMGF UMR_S910, Faculté de Médecine, 27 Bd Jean Moulin, 13385 Marseille, France Inserm, U910, Faculté de Médecine, 27 Bd Jean Moulin, 13005 Marseille, France

Aims: Heart valve maturation is achieved by the organization of extracellular matrix (ECM) and the distribution of valvular interstitial cells. However, the factors that regulate matrix components required for valvular structure and function are unknown. Based on the discovery of its specific expression in cardiac valves, we aimed to uncover the role of Krox20 (Egr-2) during valve development and disease.

Methods And Results: Using series of mouse genetic tools, we demonstrated that loss of function of Krox20 caused significant hyperplasia of the semilunar valves, while atrioventricular valves appeared normal. This defect was associated with an increase in valvular interstitial cell number and ECM volume. Echo Doppler analysis revealed that adult mutant mice had aortic insufficiency. Defective aortic valves (AoVs) in Krox20(-/-) mice had features of human AoV disease, including excess of proteoglycan deposition and reduction of collagen fibres. Furthermore, examination of diseased human AoVs revealed decreased expression of KROX20. To identify downstream targets of Krox20, we examined expression of fibrillar collagens in the AoV leaflets at different stages in the mouse. We found significant down-regulation of Col1a1, Col1a2, and Col3a1 in the semilunar valves of Krox20 mutant mice. Utilizing in vitro and in vivo experiments, we demonstrated that Col1a1 and Col3a1 are direct targets of Krox20 activation in interstitial cells of the AoV.

Conclusion: This study identifies a previously unknown function of Krox20 during heart valve development. These results indicate that Krox20-mediated activation of fibrillar Col1a1 and Col3a1 genes is crucial to avoid postnatal degeneration of the AoV leaflets.
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http://dx.doi.org/10.1093/cvr/cvu233DOI Listing
December 2014

Distinct molecular strategies for Hox-mediated limb suppression in Drosophila: from cooperativity to dispensability/antagonism in TALE partnership.

PLoS Genet 2013 7;9(3):e1003307. Epub 2013 Mar 7.

Centre National de la Recherche Scientifique, Aix Marseille Université, Institut de Biologie du Développement de Marseille Luminy, UMR 7288, Parc Scientifique de Luminy, Marseille, France.

The emergence following gene duplication of a large repertoire of Hox paralogue proteins underlies the importance taken by Hox proteins in controlling animal body plans in development and evolution. Sequence divergence of paralogous proteins accounts for functional specialization, promoting axial morphological diversification in bilaterian animals. Yet functionally specialized paralogous Hox proteins also continue performing ancient common functions. In this study, we investigate how highly divergent Hox proteins perform an identical function. This was achieved by comparing in Drosophila the mode of limb suppression by the central (Ultrabithorax and AbdominalA) and posterior class (AbdominalB) Hox proteins. Results highlight that Hox-mediated limb suppression relies on distinct modes of DNA binding and a distinct use of TALE cofactors. Control of common functions by divergent Hox proteins, at least in the case studied, relies on evolving novel molecular properties. Thus, changes in protein sequences not only provide the driving force for functional specialization of Hox paralogue proteins, but also provide means to perform common ancient functions in distinct ways.
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http://dx.doi.org/10.1371/journal.pgen.1003307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3591290PMC
June 2013

Reiterative use of signalling pathways controls multiple cellular events during Drosophila posterior spiracle organogenesis.

Dev Biol 2010 Jul 18;343(1-2):18-27. Epub 2010 Apr 18.

Institut de Biologie du Développement de Marseille Luminy, IBDML, CNRS, Université de la Méditerranée, Parc Scientifique de Luminy, Case 907 13288 Marseille Cedex 09, France.

Organogenesis proceeds in multiple steps and events that need to be coordinated in time and space. Yet the genetic and molecular control of such coordination remains poorly understood. In this study we have investigated the contribution of three signalling pathways, Wnt/Wingless (Wg), Hedgehog (Hh), and epidermal growth factor receptor (EGFR), to posterior spiracle morphogenesis, an organ that forms under Abdominal-B (AbdB) control in the eighth abdominal segment. Using targeted signalling inactivation, we show that these pathways are reiteratively used to control multiple cellular events during posterior spiracle organogenesis, including cell survival and maintenance of cell polarity and adhesion required for tissue integrity. We propose that the reiterative use of the Wg, Hh, and EGFR signalling pathways serves to coordinate in time and space the sequential deployment of events that collectively allow proper organogenesis.
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http://dx.doi.org/10.1016/j.ydbio.2010.04.001DOI Listing
July 2010

Telomeric trans-silencing in Drosophila melanogaster: tissue specificity, development and functional interactions between non-homologous telomeres.

PLoS One 2008 Sep 22;3(9):e3249. Epub 2008 Sep 22.

Laboratoire "Dynamique du Génome et Evolution", Institut Jacques Monod, UMR7592, CNRS-Universités Paris 6 et 7, Paris, France.

Background: The study of P element repression in Drosophila melanogaster led to the discovery of the telomeric Trans-Silencing Effect (TSE), a homology-dependent repression mechanism by which a P-transgene inserted in subtelomeric heterochromatin (Telomeric Associated Sequences, "TAS") has the capacity to repress in trans, in the female germline, a homologous P-lacZ transgene located in euchromatin. TSE can show variegation in ovaries, displays a maternal effect as well as an epigenetic transmission through meiosis and involves heterochromatin and RNA silencing pathways.

Principal Findings: Here, we analyze phenotypic and genetic properties of TSE. We report that TSE does not occur in the soma at the adult stage, but appears restricted to the female germline. It is detectable during development at the third instar larvae where it presents the same tissue specificity and maternal effect as in adults. Transgenes located in TAS at the telomeres of the main chromosomes can be silencers which in each case show the maternal effect. Silencers located at non-homologous telomeres functionally interact since they stimulate each other via the maternally-transmitted component. All germinally-expressed euchromatic transgenes tested, located on all major chromosomes, were found to be repressed by a telomeric silencer: thus we detected no TSE escaper. The presence of the euchromatic target transgene is not necessary to establish the maternal inheritance of TSE, responsible for its epigenetic behavior. A single telomeric silencer locus can simultaneously repress two P-lacZ targets located on different chromosomal arms.

Conclusions And Significance: Therefore TSE appears to be a widespread phenomenon which can involve different telomeres and work across the genome. It can explain the P cytotype establishment by telomeric P elements in natural Drosophila populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0003249PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2547894PMC
September 2008

Liprin-alpha has LAR-independent functions in R7 photoreceptor axon targeting.

Proc Natl Acad Sci U S A 2006 Aug 24;103(31):11595-600. Epub 2006 Jul 24.

Skirball Institute for Biomolecular Medicine, Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.

In the Drosophila visual system, the color-sensing photoreceptors R7 and R8 project their axons to two distinct layers in the medulla. Loss of the receptor tyrosine phosphatase LAR from R7 photoreceptors causes their axons to terminate prematurely in the R8 layer. Here we identify a null mutation in the Liprin-alpha gene based on a similar R7 projection defect. Liprin-alpha physically interacts with the inactive D2 phosphatase domain of LAR, and this domain is also essential for R7 targeting. However, another LAR-dependent function, egg elongation, requires neither Liprin-alpha nor the LAR D2 domain. Although human and Caenorhabditis elegans Liprin-alpha proteins have been reported to control the localization of LAR, we find that LAR localizes to focal adhesions in Drosophila S2R+ cells and to photoreceptor growth cones in vivo independently of Liprin-alpha. In addition, Liprin-alpha overexpression or loss of function can affect R7 targeting in the complete absence of LAR. We conclude that Liprin-alpha does not simply act by regulating LAR localization but also has LAR-independent functions.
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http://dx.doi.org/10.1073/pnas.0604766103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1544215PMC
August 2006
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