Fiche Projet - Ecole Doctorale Complexité du vivant

Ecole Doctorale COMPLEXITE DU VIVANT – Fiche Projet CONCOURS
Nom et prénom du directeur de thèse (et si besoin du co-directeur) :
Sophie Vriz et Alain Joliot
Le directeur de thèse et le co-directeur doivent impérativement être habilités à diriger les recherches (HDR)
Coordonnées
Sophie Vriz Tel : 014427-1454
Alain Joliot : Tel : 014427-1470
e-mail : [email protected]
e-mail : [email protected]
Nom et prénom du responsable de l’équipe : Sophie Vriz et Alain Joliot
Nombre de chercheurs et enseignants-chercheurs statutaires de l’équipe titulaires d’une HDR :
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Nom et prénom du responsable du laboratoire : Alain Prochiantz
Intitulé du laboratoire et N° d’unité : Centre Interdisciplinaire de Recherche en Biologie (CIRB)
Collège de France Cnrs/ Umr 7241 - Inserm U1050
Spécialité : Biologie cellulaire, Biologie du développement
Titre du projet de thèse : Hoxa13 paracrine and intracrine activities during zebrafish development and
regeneration
Résumé du projet de thèse (1 page maximum, en anglais)
Homeoproteins (HP) constitute a major class of transcription factors active throughout development and
in adulthood. They have the unique property of transfer from cell to cell by nonconventional mechanisms. This
intercellular transfer confers to the protein genuine paracrine activity that has been so far associated with
morphogenesis and axon guidance during embryonic development, cortical plasticity, and cell survival in
response to oxidative stress in the adult. We have recently shown that in cell culture, oxydation regulates
Engrailed intercellular transfer (manuscript in preparation). Indeed, reactive oxygen species, appears to have
multiple regulatory and signalling properties in diverse physiological processes. In the adult zebrafish, H2O2 is
required for the early phases of caudal fin regeneration and later for axon regrowth. H2O2 also participates to
axon growth in embryos. Because homeoproteins are keys regulators of morphogenetic processes, including
axon guidance, we hypothesized that they could be targets of H2O2 action, notably by the regulation of the
balance between intracrine and paracrine actions. To test this new paradigm we chose HOXA13 protein.
HOXA13 is encoded by the last gene of the hoxA complex. It controls the development of distal parts of the em
and its function in limb- as well as tail-bud development has been well documented in distant evolutionary models inc
human, in which hoxA13 mutation induces the hand-foot-genital syndrome. HoxA13 is re-expressed during woundin
regeneration in adult zebrafish and HOXA13 protein has been found in the extracellular matrix of wounds in mammals [
auf dem Keller, ETH, Zurich, personal communication]. In zebrafish, two hoxA13 genes a & b are present from duplicati
they have diverged enough to have non-redundant activities. We have obtained a zebrafish hoxA13b mutant strain that
abnormal tail bud and pectoral fin development.
The aim of this project is first to decipher the respective roles of HoxA13b intracrine and paracrine
activities in the development of pectoral fin and of tail bud in zebrafish and in parallel, to evaluate the role of
H2O2 in HoxA13b intercellular transfer starting from cell culture models. Preliminary experiments confirm
HoxA13b secretion in cell culture and the efficiency of HoxA13b intercellular transfer in vivo will be quantified
with already validated protocols. Rescue experiments of the hoxA13b mutant will be performed with different
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Ecole Doctorale COMPLEXITE DU VIVANT – Fiche Projet CONCOURS
forms of HoxA13b (deficient for secretion or internalisation). In this first part, we expect to characterize the
relative contribution of paracrine and intracrine activities of HoxA13b during development.
Others and we have demonstrated that H2O2 levels are highly dynamic during development, both at the
spatial and temporal levels. To address the functional consequences of this modulation, we have established
genetic and pharmaceutical treatments to manipulate H2O2 levels in cell culture and in vivo (Meda et al, in
preparation). These tools will be used to decipher the role of H2O2 in HoxA13b function. The intercellular
transfer and transcriptional activity of HoxA13b will be analysed in cell culture in response to H2O2 modulation.
We will take advantage of on-going strategies aiming at down regulating H2O2 levels in vivo in a controlled way
to address the contribution of H2O2 in pectoral fin and tail bud development, in particular through the regulation
of HoxA13 function.
Thèses actuellement en cours dans l’équipe
Nom et Prénom du doctorant
Francesca Meda
Nom du directeur de thèse
Sophie Vriz & Alain Joliot
Année de 1ere
inscription et
Ecole Doctorale
2013 - CdV
Financement pendant la thèse
Labex Memolife puis ATER
(Collège de France)
Trois publications récentes du directeur de thèse .Mettre en gras le nom du directeur de thèse.
Sophie Vriz:
- Gauron C, Rampon C, Bouzaffour M, Ipendey E, Teillon J, Volovitch M, Vriz S (2013) Sustained production of ROS
triggers compensatory proliferation and is required for regeneration to proceed. Scientific Reports 3: 2084
- Gautier A, Gauron C, Volovitch M, Bensimon D, Jullien L, Vriz S (2014) How to control proteins with light
in living systems. Nature Chem Biol 10(7): 533-41
- Meda F, Gauron C, Rampon C, Teillon J, Volovitch M, Vriz S. (2016) Nerves control RedOx level in mature
tissues through Schwann cells and Shh signaling. Antioxidants and Redox Signaling, 24(6):299-311.
Alain Joliot:
- Layalle S, Volovitch M, Mugat B, Bonneaud N, Parmentier ML, Prochiantz A, Joliot A, Maschat F. (2011)
Engrailed homeoprotein acts as a signaling molecule in the developing fly. Development 138(11):2315-23.
- Sagan S, Burlina F, Alves ID, Bechara C, Dupont E, Joliot A (2013) Homeoproteins and homeoprotein-derived
peptides: going in and out. Curr Pharm 19(16):2851-62.
- Rampon C*, Gauron C*, Lin T, Meda F, Dupont E, Cosson A, Ipendey I, Frerot A, Aujard I, Le Saux T,
Bensimon D, Jullien L, Volovitch M, Vriz S, Joliot A (2015) Control of brain patterning by Engrailed paracrine
transfer: a new function of the PBX interaction domain. Development, 142(10):1840-9.
Docteurs encadrés par le directeur de thèse ayant soutenu après septembre 2010 et publications relatives à leur sujet
de thèse. Mettre en gras le nom du directeur de thèse et celui du docteur.
Nom Prénom : Carole Gauron
Date de soutenance : 22 septembre 2014
Durée de thèse (en mois): 36 mois
Ecole Doctorale : Interdisciplinaire pour le vivant » (iViv)
Publications :
. Gauron C, Rampon C, Bouzaffour M, Ipendey E, Teillon J, Volovitch M, Vriz S (2013) Sustained production of
ROS triggers compensatory proliferation and is required for regeneration to proceed. Scientific Reports 3: 2084
. Rampon C*, Gauron C*, Meda F, Volovitch M, Vriz S (2014) Adenosine enhances progenitor cell recruitment and
nerve growth via its A2B receptor during adult fin regeneration. Purinergic Signalling 10: 595-602
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Ecole Doctorale COMPLEXITE DU VIVANT – Fiche Projet CONCOURS
. Rampon C*, Gauron C*, Lin T, Meda F, Dupont E, Cosson A, Ipendey I, Frerot A, Aujard I, Le Saux T, Bensimon D,
Jullien L, Volovitch M, Vriz S*, Joliot A*, (2015) Control of brain patterning by Engrailed paracrine transfer: a new
function of the PBX interaction domain. Development, 142(10):1840-9.
. Meda F*, Gauron C*, Rampon C*, Teillon J, Volovitch M, Vriz S. (2015) Nerves control RedOx level in mature
tissues through Schwann cells and Shh signaling. Antioxidants and Redox Signaling, 24(6):299-311.
- Gauron C, Meda F, Dupont E, Quenech’Du N, Ipendey E, Volovitch M, Del Bene F, Joliot A, Rampon C, Vriz S.
Hydrogen peroxide (H2O2) controls axon pathfinding during zebrafish development. Dev Biol Under revision.
Nom Prénom : Thibault Lin
Date de soutenance : 24 septembre 2015
Durée de thèse (en mois): 48 mois
Ecole Doctorale : Compléxité du Vivant
Publications :
. Rampon C*, Gauron C*, Lin T, Meda F, Dupont E, Cosson A, Ipendey I, Frerot A, Aujard I, Le Saux T, Bensimon D,
Jullien L, Volovitch M, Vriz S, Joliot A, (2015) Control of brain patterning by Engrailed paracrine transfer: a new
function of the PBX interaction domain. Development, 142(10):1840-9.
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