Characterization of the rabconectin

ED BIO SORBONNE PARIS CITE Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2016-2017
Renseignements relatifs à l’Unité de Recherche :
Label et intitulé : U1141. PROTECT
Nom et prénom du Directeur : Pierre Gressens
Téléphone : 01 40 03 19 85
Télécopie :
Courriel: [email protected]
Renseignements relatifs à l’Equipe :
Nom de l’Equipe d’Accueil : Maladies génétiques du cerveau en développement.
Nom et prénom du responsable : Pierre Gressens
Qualité du responsable : Directeur de Recherche
Téléphone :
Télécopie :
Courriel : [email protected]
Renseignements relatifs au sujet de thèse :
Nom et prénom du Directeur de thèse (HDR) : Nicolas de Roux
Qualité : PU-PH
Téléphone :
01 40 03 19 85
Télécopie :
Courriel : [email protected]
Titre du sujet proposé : Caractérisation de la fonction de la rabconectin-3a dans la maturation des
neurones GnRH à la puberté.
Characterization of the rabconectin-3α function in GnRH neuron maturation at puberty.
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) :
The reactivation of GnRH neurons at the end of childhood marks the initiation of puberty. It is the output
of a neurodevelopmental program starting during development. We recently demonstrated that the
expression level of Dmxl2 encoding the synaptic protein, rabconnectin-3α, determines the maturation of
GnRH neurons. In this project, the molecular mechanism leading to GnRH deficiency in mice expressing
low levels of Dmxl2 will be characterized. New insights on the pathogenesis pubertal disorders are
expected.
Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2016-2017
Nom, prénom du directeur de l'unité de recherche : Pierre Gressens
Numéro de l'unité de recherche (et établissement de rattachement) : U1141. Université Paris Diderot
Nom, prénom du responsable de l'équipe d'accueil (EAD) : Pierre Gressens
Nom, prénom du directeur de thèse : Nicolas de Roux
Titre du sujet de thèse proposé : Characterization of the rabconectin-3α function in GnRH neuron
maturation at puberty
Citer 5 mots clés : GnRH neuron. Puberty. Neuronal maturation. Synapses. Plasticity
Candidat pressenti :
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OUI
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NON
Contenu scientifique du programme de la thèse (en anglais)
Several phases of activation and inactivation of the GnRH network are required to obtain normal
reproduction function in adulthood: during prenatal development, just after birth, at puberty and in adults.
During the last decade, mechanisms of the pubertal onset of GnRH neurons activation have been better
understood. By the end of childhood, the GnRH network must integrate inhibitory and excitatory inputs
from multiple afferent neurons in a timely, homeostatic fashion with peripheral hormones for the proper
reactivation of the HPG axis. The main consequence of this maturation is the increase of GnRH
secretion under the control of Kisspeptin. In addition GnRH neurons undergo from a complex
morphology to uni-/bipolar morphology. This modification is supposed to be under the control of
glutamatergic and GABAergic inputs. Puberty is thus the output of a neurodevelopmental program which
starts during development, progress slowly during childhood but accelerated at puberty.
We recently demonstrated the link between the haploinsufficiency of DMXL2 and a complex
phenotype which associates polyendocrinopathies (GnRH deficiency, growth delay, mellitus diabetes),
peripheral neuropathies and mental disability. The conditional deletion of Dmxl2 in neurons
(Nes::cre;Dmxl2loxp/wt) reproduced the GnRH deficiency. Our results also show that adult mice with a low
expression of Dmxl2 in the brain display an increased number of immature GnRH neurons and no
response to kisspeptin. These defects are not due to the low expression of Dmxl2 in GnRH neurons.
Dmxl2 encodes rabconectin-3α, a synaptic protein which interacts with proteins involved in the control of
Rab3 activation as well as with different subunits of the vesicular-ATPase. The expression level of a
protein involved in the control of the secretory pathway therefore controls the maturation of a
neuroendocrine network.
The aim of this thesis is to delineate the molecular mechanism leading to GnRH deficiency in
Nes::cre;Dmxl2loxp/wt mice. An in-vivo model to study GnRH neuron maturation will be developed. Then,
the molecular signature due to the low expression of Dmxl2 in afferent neurons will be assessed in
GnRH neurons. The last part of this project will be to rescue the normal maturation of GnRH network in
Nes::cre;Dmxl2loxp/wt mice.
In addition to increase our understanding of the neuroendocrine control of GnRH neuron
maturation at the end of childhood, this project will give new insights on the link between a defect in the
secretory pathway and the development of neuroendocrine disorders.
Indiquez les cinq meilleures publications récentes de l’équipe :
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Boehm U, Bouloux PM, Dattani MT, de Roux N, Dode C, Dunkel L, Dwyer AA, Giacobini P, Hardelin JP, Juul A,
Maghnie M, Pitteloud N, Prevot V, Raivio T, Tena-Sempere M, Quinton R & Young J. Expert consensus document:
European Consensus Statement on congenital hypogonadotropic hypogonadism-pathogenesis, diagnosis and
treatment. Nat Rev Endocrinol 2015 11 547-564.
Tata B, Huijbregts L, Jacquier S, Csaba Z, Genin E, Meyer V, Leka S, Dupont J, Charles P, Chevenne D, Carel
JC, Leger J & de Roux N. Haploinsufficiency of dmxl2, encoding a synaptic protein, causes infertility associated
with a loss of GnRH neurons in mouse. PLoS Biol 2014 12 e1001952.
Chevrier L, de Brevern A, Hernandez E, Leprince J, Vaudry H, Guedj AM & de Roux N. PRR repeats in the
intracellular domain of KISS1R are important for its export to cell membrane. Mol Endocrinol 2013 27 1004-1014.
Villanueva C, Jacquier S & de Roux N. DLK1 is a somato-dendritic protein expressed in hypothalamic argininevasopressin and oxytocin neurons. PLoS One 2012 7 e36134.
Huijbregts L, Roze C, Bonafe G, Houang M, Le Bouc Y, Carel JC, Leger J, Alberti P & de Roux N. DNA
polymorphisms of the KiSS1 3' Untranslated region interfere with the folding of a G-rich sequence into Gquadruplex. Mol Cell Endocrinol 2012 351 239-248.