Brice Marcet

Université Côte d'Azur

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Pascal Barbry

Institut de Pharmacologie Moléculaire et Cellulaire

Laure‐Emmanuelle Zaragosi

Université Côte d'Azur

B. Chevalier

Institut Necker Enfants Malades

Kévin Lebrigand

Institut de Pharmacologie Moléculaire et Cellulaire

Virginie Magnone

Centre National de la Recherche Scientifique

Laurent Kodjabachian

Aix-Marseille Université

Agnès Paquet

Médecins Sans Frontières

Olivier Mercey

University of Geneva

Lisa Giovannini‐Chami

Fondation Lenval

Gilles Ponzio

Inserm

Cooperative Institutions

Centre National de la Recherche Scientifique

Inserm

Université Côte d'Azur

Institut de Pharmacologie Moléculaire et Cellulaire

Aix-Marseille Université

Université Libre de Bruxelles

Centre National pour la Recherche Scientifique et Technique (CNRST)

Centre Hospitalier Universitaire de Nice

Université de Lille

Observatoire de la Côte d’Azur

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MicroRNA-based silencing of Delta/Notch signaling promotes multiple cilia formation

Cell Cycle (2011)

Brice Marcet B. Chevalier Christelle Coraux Laurent Kodjabachian Pascal Barbry

Multiciliated cells lining the surface of some vertebrate epithelia are essential for various physiological processes, such as airway cleansing. Their apical surface is constituted by hundreds of motile cilia, which beat in a coordinated manner to generate directional fluid flow. We recently reported the identification of microRNAs of the miR-449 family as evolutionary conserved key regulators of vertebrate multiciliogenesis. This novel function of miR-449 was established using in vivo and in vitro antisense approaches in two distinct experimental models. miR-449 strongly accumulated in multiciliated cells in human airway epithelium and Xenopus laevis embryonic epidermis, where it triggered centriole multiplication and multiciliogenesis by directly repressing the Delta/Notch pathway. Our data complement previous reports that showed the blocking action of miR-449 on the cell cycle, and unraveled a novel conserved mechanism whereby Notch signaling must undergo microRNA-mediated inhibition to permit differentiation of ciliated cell progenitors. We review here several important questions regarding the links between microRNAs and the Notch pathway in the control of cell fate.

Motile cilium

Cell fate determination

10.4161/cc.10.17.17011

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Citations (36)

BMP signalling controls the construction of vertebrate mucociliary epithelia

Development (2015)

Marie Cibois Guillaume Luxardi B. Chevalier Virginie Thomé Olivier Mercey

Despite the importance of mucociliary epithelia in animal physiology, the mechanisms controlling their establishment are poorly understood. Using the developing Xenopus epidermis and regenerating human upper airways, we reveal the importance of BMP signalling for the construction of vertebrate mucociliary epithelia. In Xenopus, attenuation of BMP activity is necessary for the specification of multiciliated cells (MCCs), ionocytes and small secretory cells (SSCs). Conversely, BMP activity is required for the proper differentiation of goblet cells. Our data suggest that the BMP and Notch pathways interact to control fate choices in the developing epidermis. Unexpectedly, BMP activity is also necessary for the insertion of MCCs, ionocytes and SSCs into the surface epithelium. In human, BMP inhibition also strongly stimulates the formation of MCCs in normal and pathological (cystic fibrosis) airway samples, whereas BMP overactivation has the opposite effect. This work identifies the BMP pathway as a key regulator of vertebrate mucociliary epithelium differentiation and morphogenesis.

Epidermis (zoology)

Developmental Biology

10.1242/dev.118679

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Citations (45)

MicroRNAs as key regulators of GTPase-mediated apical actin reorganization in multiciliated epithelia

Small GTPases (2016)

Olivier Mercey Laurent Kodjabachian Pascal Barbry Brice Marcet

Multiciliated cells (MCCs), which are present in specialized vertebrate tissues such as mucociliary epithelia, project hundreds of motile cilia from their apical membrane. Coordinated ciliary beating in MCCs contributes to fluid propulsion in several biological processes. In a previous work, we demonstrated that microRNAs of the miR-34/449 family act as new conserved regulators of MCC differentiation by specifically repressing cell cycle genes and the Notch pathway. Recently, we have shown that miR-34/449 also modulate small GTPase pathways to promote, in a later stage of differentiation, the assembly of the apical actin network, a prerequisite for proper anchoring of centrioles-derived neo-synthesized basal bodies. We characterized several miR-34/449 targets related to small GTPase pathways including R-Ras, which represents a key and conserved regulator during MCC differentiation. Direct RRAS repression by miR-34/449 is necessary for apical actin meshwork assembly, notably by allowing the apical relocalization of the actin binding protein Filamin-A near basal bodies. Our studies establish miR-34/449 as central players that orchestrate several steps of MCC differentiation program by regulating distinct signaling pathways.

Exocyst

Small GTPase

Basal body

10.1080/21541248.2016.1151099

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Citations (13)

Combination of CRISPR-Cas9-RNP and Single-Cell RNAseq to Identify Cell State-Specific FOXJ1 Functions in the Human Airway Epithelium

Methods in molecular biology (2023)

Laure‐Emmanuelle Zaragosi Alizé Gouleau Margot Delin Kévin Lebrigand Marie‐Jeanne Arguel

10.1007/978-1-0716-3507-0_1

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Citations (1)

Des microARN au cœur de la fabrication de cils motiles

médecine/sciences (2015)

Olivier Mercey B. Chevalier Laurent Kodjabachian Pascal Barbry Brice Marcet

> Le cil, organite cellulaire conserve chez de nombreux eucaryotes, est un prolongement membranaire constitue de microtubules et dote de fonctions sensorielles et/ou locomotrices particulieres [1]. On distingue le cil primaire, non-motile et present dans la plupart des types cellulaires, du cil motile qui est present en un unique exemplaire dans des cellules « monociliees », et jusqu’a plusieurs centaines dans des cellules dites « multiciliees » (➜). Chez les vertebres, ces cellules multiciliees bordent la surface de certains tissus comme les voies respiratoires, les ventricules cerebraux, le tractus genital feminin, les placodes1 olfactives du poisson zebre ou encore l’epiderme d’embryon de grenouille [2, 3]. Grâce au battement coordonne des cils motiles, les cellules multiciliees jouent un role important dans divers processus physiologiques comme l’evacuation, par l’epithelium respiratoire, des particules inhalees piegees dans le mucus, la circulation du liquide cephalo-rachidien ou la progression de l’embryon dans le tractus genital [2]. Un dysfonctionnement ou une diminution du nombre de ces cils motiles peut etre la cause ou aggraver les symptomes de nombreuses pathologies telles que des ciliopathies (comme les dyskinesies ciliaires touchant le systeme respiratoire) ou des maladies respiratoires chroniques (comme la mucoviscidose,

10.1051/medsci/20153112010

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Role of small regulatory RNAs in normal and pathological respiratory organs

Pascal Barbry Brice Marcet Bernard Mari Nicolas Pottier Laure‐Emmanuelle Zaragosi

MiRNAs are associated with normal cellular processes and with many complex diseases in respiratory tissues. In multiciliated cells, hundreds of motile cilia beat in a coordinated manner to generate directional fluid flow. We have identified microRNAs of the miR-34/449 families as evolutionary conserved key regulators of vertebrate multiciliogenesis. miR-449 strongly accumulated in multiciliated cells in human airway epithelium and Xenopus laevis embryonic epidermis, where it triggered centriole multiplication and multiciliogenesis by directly repressing the Delta/Notch pathway. Our data unravel a novel conserved mechanism whereby Notch signaling must undergo microRNAmediated inhibition to permit differentiation of ciliated cell progenitors. We then observed an altered expression of miR-199a-5p in IPF (idiopathic fibrosis) patients, and also in the mouse bleomycin model of lung fibrosis. Increased levels of miR-199a-5p were observed in myofibroblasts from injured mouse lungs and fibroblastic foci. In cultured lung fibroblasts, miR-199a-5p expression was induced upon TGFβ exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts. The effects of miR-199a-5p as a key effector of TGFβ signaling in lung fibroblasts were explained by its effects on CAV1, a critical mediator of pulmonary fibrosis. Dysregulation of miR-199a-5p probably represents a general mechanism contributing to the fibrotic process. MiR-199a-5p thus behaves as a major regulator of tissue fibrosis with therapeutic potency to treat fibroproliferative diseases. References: Marcet B et al. Nat Cell Biol. 2011 13:693-699. CLL Cardenas et al. PLoS Genetics. 2013. In press.

Ectopic expression

Motile cilium

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Control of vertebrate multiciliogenesis by miR-449 through direct repression of the Delta/Notch pathway

Nature Cell Biology (2011)

Brice Marcet B. Chevalier Guillaume Luxardi Christelle Coraux Laure‐Emmanuelle Zaragosi

Cell fate determination

10.1038/ncb2241

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Citations (277)

Régulation de l'activité du canal chlorure CFTR : Relation avec les voies de signalisation des récepteurs nucléotidiques de type P2Y

Brice Marcet

Source

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Novel dynamics of human mucociliary differentiation revealed by single-cell RNA sequencing of nasal epithelial cultures

Development (2019)

Sandra Ruiz García Marie Deprez Kévin Lebrigand Amélie Cavard Agnès Paquet

ABSTRACT The upper airway epithelium, which is mainly composed of multiciliated, goblet, club and basal cells, ensures proper mucociliary function and can regenerate in response to assaults. In chronic airway diseases, defective repair leads to tissue remodeling. Delineating key drivers of differentiation dynamics can help understand how normal or pathological regeneration occurs. Using single-cell transcriptomics and lineage inference, we have unraveled trajectories from basal to luminal cells, providing novel markers for specific populations. We report that: (1) a precursor subgroup of multiciliated cells, which we have entitled deuterosomal cells, is defined by specific markers, such as DEUP1, FOXN4, YPEL1, HES6 and CDC20B; (2) goblet cells can be precursors of multiciliated cells, thus explaining the presence of hybrid cells that co-express markers of goblet and multiciliated cells; and (3) a repertoire of molecules involved in the regeneration process, such as keratins or components of the Notch, Wnt or BMP/TGFβ pathways, can be identified. Confirmation of our results on fresh human and pig airway samples, and on mouse tracheal cells, extend and confirm our conclusions regarding the molecular and cellular choreography at work during mucociliary epithelial differentiation.

Mucociliary clearance

10.1242/dev.177428

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Citations (262)

Late Breaking Abstract - The “one airway, one disease” concept at the light of Th2 inflammation

Lisa Giovannini‐Chami Agnès Paquet C. Sanfiorenzo Nicolas Pons Julie Cazareth

Rationale: A pathophysiologic continuum has been described between nose and bronchus in allergic respiratory diseases, but no study has directly compared gene expression profiles of nasal and bronchial epithelium in a same individual. Aims and objectives: To assess whether clinical features of the bronchi, such as Th2 inflammation status, could be recapitulated at the nasal epithelium level, in nasal and bronchial epithelia from the same individual. Methods: Twelve allergic rhinitis and asthma (AR), 14 isolated allergic rhinitis (R) and 13 healthy controls (C) were included. Nasal and bronchial cells were collected by brushings. Cellular composition was assessed by flow cytometry. Gene expression was analyzed by RNA-seq. A Th2 signature compatible for studies of bronchial and nasal epithelia was established using 4 public datasets. Results: A signature of 63 transcripts distinguished nasal and bronchial brushings, regardless of their pathological status. The Th2 specific signature stratified the samples firstly according the tissue of origin, and then according the level of the Th2 signature. Concordance between high and low Th2 status was good in AR (Cohen's kappa 0.588, p = 0.088) and C (kappa= 1, p=0.0027), but poor for R samples (kappa = 0.161, p-value=0.6). Th2 score correlated in nose and in bronchi with mastocytes counts and number of sensitizations. Of note, 4/10 R patients had a Th2-high signature in bronchi correlating with asthma history in childhood. Conclusions: Nasal and bronchial epithelia display distinct transcriptional signatures. In AR group, but not in R group, nasal cells can be used as bronchial surrogates to assess Th2 inflammation.

10.1183/1393003.congress-2017.pa4938

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