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Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2017-2018
Renseignements relatifs à l’Unité de Recherche :
Label et intitulé : UMRS1138, Centre de Recherche des Cordeliers (CRC)
Nom et prénom du Directeur : Pascal Ferré
Téléphone :
0144272432
Télécopie :
Courriel: [email protected]
Renseignements relatifs à l’Equipe :
Nom de l’Equipe d’Accueil : Physiopathologie Orale et Moléculaire
Nom et prénom du responsable : Ariane Berdal
Qualité du responsable : PU-PH
Téléphone :
0144275589
Télécopie :
Courriel : [email protected]
Renseignements relatifs au sujet de thèse :
Nom et prénom du Directeur de thèse (HDR) : Renata Kozyraki (co-direction avec Olivier Cases)
Qualité : CR1
Téléphone :
0144275590
Télécopie :
Courriel : [email protected]
Titre du sujet proposé : Endocytose multiligand et agénésie dentaire : rôle de Cubiline et Lrp2
(En français)
(En anglais) Multiligand endocytosis and dental agenesis : role of Cubilin and Lrp2
Département (cocher le département correspondant au sujet de thèse qui n’est pas obligatoirement le
vôtre) :
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Biologie Cellulaire et moléculaire, Physiologie et Physiopathologie
Immunologie
Développement Génétique Neurobiologie et Vieillissement
Infectiologie, Microbiologie
Summary (5 lines maximum) :
Kallmann syndrome is a rare genetic disorder often associated with cleft lip/palate and dental agenesis.
Although defective Fgf signaling is thought to be a causative factor, the origin of the disease remains
largely unknown. We recently identified the endocytic receptors Cubilin and Lrp2 as Fgf8 signaling
modulators. In the present proposal we wish to identify the link between these receptors, dental agenesis
and the Kallmann syndrome using mice expressing a truncated form of Cubilin.
Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2017-2087
(L’ensemble de cette fiche ne doit pas dépasser 1 page)
Nom, prénom du directeur de l'unité de recherche : Pascal Ferré
Numéro de l'unité de recherche (et établissement de rattachement) : UMRS 1138
Nom, prénom du responsable de l'équipe d'accueil (EAD) : Ariane Berdal
Nom, prénom du directeur de thèse : Renata Kozyraki
Titre du sujet de thèse proposé : Multiligand endocytosis and dental agenesis : role of Cubilin and Lrp2
(en anglais)
Citer 5 mots clés : dental agenesis, Kallmann syndrome, endocytosis, Cubn, Lrp2
(key words)
Candidat pressenti :

OUI

NON
Contenu scientifique du programme de la thèse (en anglais)
Receptor-mediated endocytosis is essential for the delivery of nutrients and the proper regulation
of signaling pathways within the cell and the entire organism. The low-density lipoprotein (LDL)
receptor-related protein (LRP) 2 is a multiligand endocytic receptor that binds to and continuously
internalizes numerous ligands including lipoproteins, proteases or vitamin-career proteins. Cubilin
(Cubn), the molecular partner of Lrp2, is a structurally unrelated endocytic receptor critical for ileal
vitamin B12 absorption, as well as for lipoprotein, transferrin and vitamin D uptake. Both receptors are
strongly expressed in the developing embryo; their function as Fgf, Bmp or Shh auxiliary receptors in the
neuroepithelium and the cephalic neural crest is necessary for normal head and face morphogenesis.
Kallmann syndrome is a rare genetic disorder characterized by central hypogonadism, the absence
of spontaneous puberty and complete or partial lack of a sense of smell. Cleft lip/palate, dental agenesis
and unilateral renal agenesis are also described in KS patients The prevalence of KS is estimated at
1/8000 males and 1/40000 in females. Despite the identification of several causative genes including
FGF8 and FGFR1, the origin of the disease is unknown in 70% of the currently identified cases (Mitchell
AL, 2011). Mutations in CUBN and LRP2 were very recently identified in such KS patients suggesting
that CUBN and LRP2 may also be involved in the pathogenesis of KS.
We generated mice constitutively expressing a truncated form of Cubn (CubnT); in these mutants
100 aminoacids were deleted in the ligand-binding region of the protein. Despite this deletion the
epithelial distribution of CubnT is not affected and the protein seems to normally interact with Lrp2.
However the homozygous mutant mice display telencephalic aplasia at early stages, aplasia/agenesis of
the caudal ganglionic eminence, choroid plexuses and rostral corpus callosum at later stages, and have
severe orofacial malformations including dental agenesis. Analysis of the mutant embryos between
embryonic days 8.5 and 10.5 suggested impaired Fgf8 signaling in the anterior head. At E18 all the
mutants analyzed showed signs of molar and/or incisor agenesis as well as bone formation defects. Our
hypothesis is that impaired Fgf signaling in CubnT mutants may at least partially explain the orofacial
defects and that CubnT mice may reproduce features of KS patients. It is of note that the introduced
deletion covers a CUBN region mutated in KS patients.
We will use immunomorphological, ultrastructural, biochemical and molecular biology
approaches to detail the orofacial and dental phenotype of the mutants and identify the underlying
molecular defect. We will particularly focus on signs of aberrant Fgf ligand/receptor expression and
signaling including the expression of the Fgf8, Fgf17, Fgf18, FgfR2 and FgfR1 or Sprouty genes in the
prospective tooth region, the differentiating ameloblasts or odontoblasts.
Indiquez les cinq meilleures publications récentes de l’équipe :
Impaired vitreous composition and retinal pigment epithelium function in the Foxg1-Lrp2 myopic
mice. Cases O, Obry A, Ben-Yacoub S, Augustin S, Joseph A, Simonutti M, Christ A, Cosette P,
Kozyraki R, BBA, 2017 Mar 30, doi: 10.1016/j.bbadis.2017.03.022
Foxg1-Cre mediated Lrp2 inactivation in the developing mouse neural retina, ciliary and retinal
pigment epithelia models congenital high myopia. Cases O, Joseph A, Obry A, Santin M, Ben-Yacoub
S, Pâques M, Amsellem S, Bribian A, Simonutti M, Augustin S, Debeir T, Sahel J, Christ A, de Castro F,
Lehéricy S, Cosette P, Kozyraki R, Plos One, 2015, 10(6):e0129518
Detailed investigations of proximal tubular function in Imerslund-Gräsbeck syndrome.
Storm T, Zeitz C, Cases O, Amsellem S, Verroust PJ, Madsen M, Benoist JF, Passemard S, Lebon S,
Jønsson IM, Emma F, Koldsø H, Hertz JM, Nielsen R, Christensen EI, Kozyraki R. BMC Med Genet.
2013 Oct 24;14(1):111. doi: 10.1186/1471-2350-14-111.
Cubilin, a high affinity receptor for fibroblast growth factor 8, is required for cell survival in the
developing vertebrate head. Cases O, Perea-Gomez A, Aguiar DP, Nykjaer A, Amsellem S, Chandellier
J, Umbhauer M, Cereghini S, Madsen M, Collignon J, Verroust P, Riou JF, Creuzet SE, Kozyraki R. J
Biol Chem. 2013 Jun 7;288(23):16655-70. doi: 10.1074/jbc.M113.451070.
Megalin mediates the influence of sonic hedgehog on oligodendrocyte precursor cell migration and
proliferation during development. Ortega MC, Cases O, Merchán P, Kozyraki R, Clemente D, de
Castro F. Glia. 2012 May;60(6):851-66. doi: 10.1002/glia.22316. Epub 2012 Feb 21.