TEAM

Biology of ciliated epithelia

Group leader : L. Kodjabachian

Our team aims to understand ciliated epithelia biology.

FOR BEGINNERS

In all vertebrates, specialized ciliated tissues are covered with cells harboring dozens of motile cilia, beating coordinately to generate directional fluid flow. Multiciliated cells help airway cleansing, ovum implantation and cerebrospinal fluid circulation.

 

Scanning Electron Microscopy photograph of the mature ciliated epidermis. Green: Multiciliated cell. Red: Mucus secretory cell (also called goblet cell). Dark brown: Smal secretory cell (produces serotonin). Yellow: Ionocyte.

Thus, several human pathologies caused by ciliary defects are characterized by chronic respiratory distress, brain abnormalities and reduced fertility. However, the biology of multiciliated cells remains poorly understood, due to the paucity of accessible in vivo models. Our team studies the embryonic skin of the amphibian Xenopus laevis, which is proving very powerful to reveal molecular and cellular principles of multiciliogenesis conserved with humans.

The Xenopus laevis embryo is easily amenable to manipulation of protein-coding genes as well as non-coding RNAs (microRNAs, long non coding RNAs) through micro-injection of mRNA constructs or antisense morpholinos, from the time of fertilization. The ciliated epidermis is particularly suited for functional analysis as it can be targeted specifically and lies at the surface of the embryo, which facilitates light and electron microscopy imaging. This tissue can also easily be exposed to pharmacological compounds and recombinant proteins at various stages of its development, and subjected to transgenesis to trace and manipulate the various cell types that compose it.

FOR SPECIALISTS
This picture shows the epidermis of a xenope tailbud-stage embryo, allowing study of ciliogenesis.

Transverse section through the epidermis of a tailbud-stage embryo. Nuclei are stained with DAPI in blue. Basal cells are stained by immunostaining against P63 in white. Multiciliated cells are stained by fluorescent in situ hybridization against alpha-tubulin in green. Ionocytes are stained by fluorescent in situ hybridization against the ATPase V1A in red.

Ciliogenesis has emerged as a key biological phenomenon in many developmental and physiological processes. Deficient ciliogenesis is the cause of numerous diseases, collectively called ciliopathies. Cilia can be motile and help generate biological fluid flows, or immotile and function as sensing and signalling platforms. Ciliogenesis is a complex process, which mobilizes several hundreds of distinct proteins. Additional complexity is coming with the differentiation into multiciliated cells that require a dramatic reorganization of the microtubular network and a 20-fold increase in the apical cell membrane.

In certain chronic airway diseases, regeneration of a functional mucociliary epithelium is important for proper healing. From this prospect, understanding the mechanisms governing the biosynthesis of multiciliated cells is a fundamental issue with high biomedical relevance.

The embryonic Xenopus laevis epidermis contains a mucociliary epithelium similar to the one covering our airways. In both cases, the epithelium is composed of mucus-secreting cells and of multiciliated cells, and represents the first line of defense against germs and pollutants. In Xenopus, the mature epithelium is set in place through four successive steps :

The four steps of ciliated epithelium formation.

Our team currently studies steps 2 to 4: i. specification of the various cell types present in the epidermis. ii. insertion of ciliated cell precursors in the superficial epithelial layer. iii. differentiation of multiciliated cells. We focus on the roles in these processes of signalling pathways and microRNAs, as the former often control cell fate decisions whereas the latter often control developmental transitions and differentiation. Our long-term goal is to generate an integrated view of the key mechanisms necessary to build and maintain the functional mucociliary epithelium that are conserved in humans.


Selected publications

PUBLICATION

CDC20B is required for deuterosome-mediated centriole production in multiciliated cells.

Revinski, DR., Zaragosi, L-E., Boutin, C., Ruiz Garcia, S., Deprez, M., Rosnet, O., Thomé, V., Mercey, O., Paquet, A., Pons, N., Marcet, B*., Kodjabachian, L*. and Barbry, P*. Equal contribution, corresponding authors*.
Nature Communications. 9:4668. PMID: 30405130

PUBLICATION

Lineage commitment of embryonic cells involves MEK1-dependent clearance of pluripotency regulator Ventx2.

Scerbo P, Marchal L, Kodjabachian L.
Elife. 2017 Jun 27;6. pii: e21526. PMID: 28654420

PUBLICATION

BMP signalling controls the construction of vertebrate mucociliary epithelia.

Cibois M, Luxardi G, Chevalier B, Thomé V, Mercey O, Zaragosi LE, Barbry P, Pasini A, Marcet B, Kodjabachian L.
Development. 2015 Jul 1;142(13):2352-63. PMID: 26092849

PUBLICATION

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

Marcet B, Chevalier B , Luxardi G , Coraux C , Zaragosi LE, Cibois M, Robbe-Sermesant K, Jolly T, Cardinaud B, Moreilhon C, Giovannini-Chami L, Nawrocki-Raby B, Birembaut P, Waldmann R, Kodjabachian L*, Barbry P*. ( co-second authors) (*co-senior authors) Highlighted on CNRS website, CNRS Le Journal and One Year with CNRS 2011.
Nat Cell Biol. 2011 Jun;13(6):693-9. PMID: 21602795

PUBLICATION

BMP inhibition initiates neural induction via FGF signaling and Zic genes.

Marchal L, Luxardi G, Thomé V, Kodjabachian L.
Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17437-42. PMID: 19805078

PUBLICATION

Notch1 is asymmetrically distributed from the beginning of embryogenesis and controls the ventral center

Castro Colabianchi, AM*, Revinski, DR*, Encinas, PI., Baez, MV., Monti, RJ., Abinal, MR., Kodjabachian, L., Franchini, LF. and López, SL.
Development. 145(14). pii: dev159368. PMID: 29866901

PUBLICATION

A Bioresistant Nitroxide Spin Label for In-Cell EPR Spectroscopy: In Vitro and In Oocytes Protein Structural Dynamics Studies.

Karthikeyan G, Bonucci A, Casano G, Gerbaud G, Abel S, Thomé V, Kodjabachian L, Magalon A, Guigliarelli B, Belle V, Ouari O, Mileo E.
Angew Chem Int Ed Engl. 2018 Jan 26;57(5):1366-1370. doi: 10.1002/anie.201710184. PMID: 29227566

PUBLICATION

Animal multicellularity and polarity without Wnt signaling.

Schenkelaars Q, Pratlong M, Kodjabachian L, Fierro-Constain L, Vacelet J, Le Bivic A, Renard E, Borchiellini C.
Sci Rep. 2017 Nov 13;7(1):15383. doi: 10.1038/s41598-017-15557-5. PMID: 29133828

PUBLICATION

Nodal–Activin pathway is a conserved neural induction signal in chordates

Yann Le Petillon, Guillaume Luxardi, Pierluigi Scerbo, Marie Cibois, Anthony Leon, Lucie Subirana, Manuel Irimia, Laurent Kodjabachian, Hector Escriva and Stephanie Bertrand
Nature Ecology & Evolution

PUBLICATION

Planar cell polarity in ciliated epithelia.

Walentek, P., Boutin, C. and Kodjabachian, L.
Cell Polarity in Development and Disease (ed. DW Houston), Elsevier.

PUBLICATION

Identification of p62/SQSTM1 as a component of non-canonical Wnt VANGL2-JNK signalling in breast cancer.

Puvirajesinghe TM, Bertucci F, Jain A, Scerbo P, Belotti E, Audebert S, Sebbagh M, Lopez M, Brech A, Finetti P, Charafe-Jauffret E, Chaffanet M, Castellano R, Restouin A, Marchetto S, Collette Y, Gonçalvès A, Macara I, Birnbaum D, Kodjabachian L, Johansen T, Borg JP.
Nat Commun. 2016 Jan 12;7:10318. PMID: 26754771

PUBLICATION

The PTK7 and ROR2 Protein Receptors Interact in the Vertebrate WNT/Planar Cell Polarity (PCP) Pathway

Martinez S, Scerbo P, Giordano M, Daulat AM, Lhoumeau AC, Thomé V, Kodjabachian L, Borg JP.
J Biol Chem. 2015 Dec 18;290(51):30562-72. PMID: 26499793

PUBLICATION

miR-34/449 control apical actin network formation during multiciliogenesis through small GTPase pathways

Chevalier B, Adamiok A, Mercey O, Revinski DR, Zaragosi LE, Pasini A, Kodjabachian L, Barbry P, Marcet B.
Nat Commun. 2015 Sep 18;6:8386. PMID: 26381333

PUBLICATION

Induction and Differentiation of the Xenopus Ciliated Embryonic Epidermis.

Cibois, M., Scerbo, P., Thomé, V., Pasini, A. and Kodjabachian, L.
Xenopus Development (eds M. Kloc and J. Z. Kubiak), John Wiley & Sons, Inc, Oxford. doi: 10.1002/9781118492833.ch7

PUBLICATION

Dysregulation of Wnt Inhibitory Factor 1 (Wif1) expression result in aberrant Wnt-β-catenin signaling and cell death of the cloaca endoderm, and anorectal malformations.

Ng RC, Matsumaru D, Ho AS, Garcia-Barceló MM, Yuan ZW, Smith D, Kodjabachian L, Tam PK, Yamada G, Lui VC
Cell Death Differ. 2014 Jun;21(6):978-89. PMID: 24632949

PUBLICATION

Xenopus embryonic epidermis as a mucociliary cellular ecosystem to assess the effect of sex hormones in a non-reproductive context.

Castillo-Briceno P, Kodjabachian L.
Front Zool. 2014 Feb 6;11(1):9. PMID: 24502321

PUBLICATION

On the Origin and Evolutionary History of NANOG.

Scerbo P, Markov GV, Vivien C, Kodjabachian L, Demeneix B, Coen L, Girardot F.
PLoS One. 2014 Jan 17;9(1):e85104. PMID: 24465486

PUBLICATION

A gene regulation network controlled by Celf1 protein-rbpj mRNA interaction in Xenopus somite segmentation.

Cibois M, Gautier-Courteille C, Kodjabachian L, Paillard L.
Biol Open. 2013 Aug 30;2(10):1078-83. PMID: 24167718

PUBLICATION

The human PDZome: a gateway to PDZ mediated functions.

Belotti E, Polanowska J, Daulat AM, Audebert S, Thome V, Lissitzky JC, Lembo F, Biblek K, Omi S, Lenfant N, Gangar A, Montcouquiol M, Santoni MJ, Sebbagh M, Aurrand-Lions M, Angers S, Kodjabachian L, Reboul J, Borg JP.
Mol Cell Proteomics. 2013 May 30. PMID: 23722234

PUBLICATION

Ventx factors function as Nanog-like guardians of developmental potential in Xenopus.

Scerbo P, Girardot F, Vivien C, Markov GV, Luxardi G, Demeneix B, Kodjabachian L, Coen L.
PLoS One. 2012;7(5):e36855. PMID: 22606298

PUBLICATION

An essential role for transcription before the MBT in Xenopus laevis.

Skirkanich J, Luxardi G, Yang J, Kodjabachian L, Klein PS.
Dev Biol. 2011 Sep 15;357(2):478-91. PMID: 21741375

PUBLICATION

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

Marcet B, Chevalier B, Coraux C, Kodjabachian L, Barbry P.
Cell Cycle. 2011 Sep 1;10(17):2858-64. PMID: 21857154

PUBLICATION

MicroRNA control biosynthesis of motile cilia in vertebrates.

Chevalier B, Kodjabachian L, Coraux C, Barbry P, Marcet B.
Med Sci (Paris). 2011 Jun-Jul;27(6-7):671-3. PMID: 21718654

PUBLICATION

PTK7: a cell polarity receptor with multiple facets.

Lhoumeau AC, Puppo F, Prébet T, Kodjabachian L, Borg JP.
Cell Cycle. 2011 Apr 15;10(8):1233-6. PMID: 21415598

PUBLICATION

Protein tyrosine kinase 7 has a conserved role in Wnt/β-catenin canonical signalling.

Puppo F*, Thomé V*, Lhoumeau AC, Cibois M, Gangar A, Lembo F, Belotti E, Marchetto S, Lécine P, Prébet T, Sebbagh M, Shin WS, Lee ST, Kodjabachian L ¶ , Borg JP ¶ . (*co-first authors) (¶ co-first authors)  
EMBO Rep. 2011 Jan;12(1):43-9. PMID: 21132015

PUBLICATION

Distinct Xenopus Nodal ligands sequentially induce mesendoderm and control gastrulation movements in parallel to the Wnt/PCP pathway.

Luxardi G, Marchal L, Thomé V, Kodjabachian L.
Development. 2010 Feb;137(3):417-26. PMID: 20056679

PUBLICATION

Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice.

Kansara M, Tsang M, Kodjabachian L, Sims NA, Trivett MK, Ehrich M, Dobrovic A, Slavin J, Choong PF, Simmons PJ, Dawid IB, Thomas DM.
J Clin Invest. 2009 Apr;119(4):837-51. PMID: 19307728

PUBLICATION

Neural induction in Xenopus requires early FGF signalling in addition to BMP inhibition.

Delaune E, Lemaire P, Kodjabachian L.
Development. 2005 Jan;132(2):299-310. PMID: 15590738

PUBLICATION

Role of Siamois before and during gastrulation. In Gastrulation : From cells to embryo

Kodjabachian L, and Lemaire P.

New-York : Cold Spring Harbor Laboratory Press. (2004) (ed. C.D. Stern), pp 609-617

PUBLICATION

Siamois functions in the early blastula to induce Spemann's organiser.

Kodjabachian L, Lemaire P.
Mech Dev. 2001 Oct;108(1-2):71-9. PMID: 11578862

PUBLICATION

Morphogen gradients: nodal enters the stage.

Kodjabachian L.
Curr Biol. 2001 Aug 21;11(16):R655-8. PMID: 11525759

PUBLICATION

A study of Xlim1 function in the Spemann-Mangold organizer.

Kodjabachian L, Karavanov AA, Hikasa H, Hukriede NA, Aoki T, Taira M, Dawid IB.
Int J Dev Biol. 2001;45(1):209-18. PMID: 11291848

PUBLICATION

A new secreted protein that binds to Wnt proteins and inhibits their activities.

Hsieh JC*, Kodjabachian L*, Rebbert ML, Rattner A, Smallwood PM, Samos CH, Nusse R, Dawid IB, Nathans J. (*co-first authors)
Nature. 1999 Apr 1;398(6726):431-6. PMID: 10201374

PUBLICATION

Embryonic induction: is the Nieuwkoop centre a useful concept?

Kodjabachian L, Lemaire P.
Curr Biol. 1998 Dec 17-31;8(25):R918-21. PMID: 9889093

PUBLICATION

A role for the vegetally expressed Xenopus gene Mix.1 in endoderm formation and in the restriction of mesoderm to the marginal zone.

Lemaire P, Darras S, Caillol D, Kodjabachian L.
Development. 1998 Jul;125(13):2371-80. PMID: 9609820

PUBLICATION

Mutations in ccf, a novel Drosophila gene encoding a chromosomal factor, affect progression through mitosis and interact with Pc-G mutations.

Kodjabachian L, Delaage M, Maurel C, Miassod R, Jacq B, Rosset R.
EMBO J. 1998 Feb 16;17(4):1063-75. PMID: 9463384

PUBLICATION

The vertebrate organizer: structure and molecules.

Lemaire P, Kodjabachian L.
Trends Genet. 1996 Dec;12(12):525-31. PMID: 9257536

PUBLICATION

The homeobox gene Siamois is a target of the Wnt dorsalisation pathway and triggers organiser activity in the absence of mesoderm.

Carnac G, Kodjabachian L, Gurdon JB, Lemaire P.
Development. 1996 Oct;122(10):3055-65. PMID: 8898219

Interactions

IBDM
NATIONAL
  • Barbry Team, Institute of Molecular and Cellular Pharmacology (Sophia-Antipolis)
  • Borg Team, Cancer Research Center of Marseille
  • Azimzadeh Team, Institut Jacques Monod (Paris)

Funding

Kodjabachian team, who studies ciologenesis and MicroRNAs is funded by the ANR

Kodjabachian team, who studies mucociliary epithelium and ciologenesis is funded by the Institut National du Cancer

Kodjabachian team, who studies ciliated epithelium on xenope is funded by the Fondation de Recherche Médicale

Kodjabachian team, who studies MicroRNAs is funded by the Association pour la Recherche contre le Cancer

ligue-cancer

Members more

Camille Boutin   Aude Nommick Andrea Pasini Diego Revinski Olivier Rosnet Virginie Thome  
Laurent Kodjabachian
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Laurent Kodjabachian

Researcher

Camille Boutin
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Camille Boutin

Researcher

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Alexandre Chuyen

PhD student

Aude Nommick
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Aude Nommick

PhD student

Andrea Pasini
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Andrea Pasini

Researcher

Diego Revinski
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Diego Revinski

Researcher

Olivier Rosnet
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Olivier Rosnet

Researcher

Virginie Thome
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Virginie Thome

Technical staff

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Marie Zilliox

MSc student

Alumni

  • Marie Cibois, Post-doc
  • Anna Adamiok, PhD
  • Patricia Castillo-Briceno, Post-doc
  • Guillaume Luxardi, PhD
  • Leslie Marchal, PhD
  • Emilie Delaune, PhD

Overview

Model organism
Biological process studied
  • Construction of a ciliated epithelium
Biological techniques
  • Micro-injection
  • Micro-surgery
  • Fluorescent In Situ Hybridization
  • Immunohistochemistry
  • Real-time PCR
  • Confocal microscopy
  • Electron microscopy
  • Morpholino-mediated knockdown

Links

Xenbase : Xenopus laevis and Xenopus tropicalis biology and genomics resource