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Perinatal Imprintings and Neurodevelopmental Disorders

Scientific Interest

Prader-Willi Syndrome (PWS) is a complex and rare neurogenetic disease characterized by a range of physiological, endocrine, cognitive and behavioural disturbances, which might be considered as a lack of adaptation of the organism to the environment. The cause of this disease is genetic and the candidate genes are all regulated by the genomic imprinting, a mechanism leading to a paternal expression of those genes, the maternal alleles being normally silenced. In our team, using mouse models genetically modified, we study the physiopathological and physiological role of two candidate genes involved in PWS: the Necdin and Magel2 genes; both genes belong to the same family of MAGE genes whose the function is still enigmatic.
Our project focused on the phenotype investigation of these mouse mutants. The abrogation of Necdin leads to a partial early post-natal lethality due to respiratory distress (in 30% of cases), to a growth retardation, sensory-motor defects and behavioural alterations. Cellular investigations of the sensory and motor deficits revealed that Necdin is an anti-apoptotic factor in developing sensory neurons and motor neurons. On the other hand, investigations of the breathing deficit in Necdin KO mice showed an alteration of the regulatory systems of the Respiratory Rhythm Generator (RRG); a dysfunction of the serotonergic system in Necdin-KO mice, known to play a crucial role in maturation and function of the central respiratory system, might be the cause of this deficit Magel2 paternal deletion results in a fatal neonatal failure to thrive due to feeding problems; this phenotype is rescued by oxytocin administration.
Our results show a crucial role of oxytocin in feeding behaviour at birth. Adult mutant mice bypassing this lethality display growth retardation, hormonal, metabolic and circadian activity alterations.These in vivo studies on mouse models are very important to understand the PWS. Beyond that, they reveal new physiological, cellular and molecular neuronal pathways involve in vital functions, which might be altered in other diseases.

Scientific Projects

  • aOxytocinergic Alterations
  • bSerotonopathy
  • cGenetics and Epigenetics

Oxytocinergic Alterations

Role of Magel2 in the development of oxytocin network neuroarchitecture



Role of Necdin in the development of amine network neuroarchitecture


Genetics and Epigenetics

Expression of the maternal allele – gene therapy

In Brief

Key words

Genomic imprinting, Prader-Willi, Necdin, Magel2, oxytocin, feeding behaviour, serotonin, respiratory distress.

Experimental Approaches

Creation and studies of mouse models genetically modified. Histology, cellular and molecular biology, imaging, stereotaxia and virus injection .



Dr Pascale Durbec, Institut de Biologie du Développement de Marseille, IBDM, France
Dr Claude Villard, Protéomique et Innovation Technologique Timone, MaP-IBiSA platform, Marseille, France

National :

Pr. Maithe Tauber, Service Pédiatrie CHU Purpan Toulouse, France
Dr Michel Désarménien, Institut de Génomique Fonctionnel, IGF, Montpellier, France
Dr laurent Bezin, Centre de Recherche en Neurosciences de Lyon, CRNL, France

International :

Dr Bice Chini, Université de Milan, Italie
Dr Valery Grinewich, Max Plant Institute, Allemagne
Dr Rachel Wevrick, Université de l’Alberta, Canada



ANR: Programme Blanc , PRAGEDER 2009-2013
Associaton Prader-Willi France: 2014
Fondation Américaine Prader-Willi: 2014
Fondation Le Jeune: 2013-2014
ANR: Programme Bien être et Santé: PRADOX 2014-2018


Join our team

Our Team has open positions for undergraduate students, PhD students and post-doctoral fellows. Applications should be sent to francoise.muscatelli@inserm.fr


Geib Sandrine, Postdoc (2005-2008)
Andrieu David , PhD (2002- 2006)
Marie-Solenne Félix, PhD (2009-2012)
Anne Rieusset, PhD (2009-2013)
Diabé Diabira, Technicien (2003-2022)
Julie Buron , PhD (2019-2023)

Nos publications

An Early Postnatal Oxytocin Treatment Prevents Social and Learning Deficits in Adult Mice Deficient for Magel2, a Gene Involved in Prader-Willi Syndrome and Autism.

Meziane H, Schaller F, Bauer S, Villard C, Matarazzo V, Riet F, Guillon G, Lafitte D, Desarmenien MG, Tauber M, Muscatelli F

Biological psychiatry - Nov 2014

Necdin shapes serotonergic development and SERT activity modulating breathing in a mouse model for Prader-Willi syndrome.

Matarazzo V, Caccialupi L, Schaller F, Shvarev Y, Kourdougli N, Bertoni A, Menuet C, Voituron N, Deneris E, Gaspar P, Bezin L, Durbec P, Hilaire G, Muscatelli F

eLife - Oct 2017

PreBötzinger complex neurons drive respiratory modulation of blood pressure and heart rate.

Menuet C, Connelly AA, Bassi JK, Melo MR, Le S, Kamar J, Kumar NN, McDougall SJ, McMullan S, Allen AM

eLife - Jun 2020

Excessive Respiratory Modulation of Blood Pressure Triggers Hypertension.

Menuet C, Le S, Dempsey B, Connelly AA, Kamar JL, Jancovski N, Bassi JK, Walters K, Simms AE, Hammond A, Fong AY, Goodchild AK, McMullan S, Allen AM

Cell metabolism - Mar 2017

Impaired regulation of KCC2 phosphorylation leads to neuronal network dysfunction and neurodevelopmental pathology.

Pisella LI, Gaiarsa JL, Diabira D, Zhang J, Khalilov I, Duan J, Kahle KT, Medina I

Science signaling - Oct 2019

The adipocyte hormone leptin sets the emergence of hippocampal inhibition in mice.

Dumon C, Diabira D, Chudotvorova I, Bader F, Sahin S, Zhang J, Porcher C, Wayman G, Medina I, Gaiarsa JL

eLife - Aug 2018

Oxytocin Signaling in the Early Life of Mammals: Link to Neurodevelopmental Disorders Associated with ASD.

Muscatelli F, Desarménien MG, Matarazzo V, Grinevich V

Current topics in behavioral neurosciences - Aug 2017

Natural breaking of the maternal silence at the mouse and human imprinted Prader-Willi locus: A whisper with functional consequences.

Matarazzo V, Muscatelli F

Rare diseases (Austin, Tex.) - Jan 2013

Ontogenesis of oxytocin pathways in the mammalian brain: late maturation and psychosocial disorders.

Grinevich V, Desarménien MG, Chini B, Tauber M, Muscatelli F

Frontiers in neuroanatomy - Jan 2014

Stochastic loss of silencing of the imprinted Ndn/NDN allele, in a mouse model and humans with prader-willi syndrome, has functional consequences.

Rieusset A, Schaller F, Unmehopa U, Matarazzo V, Watrin F, Linke M, Georges B, Bischof J, Dijkstra F, Bloemsma M, Corby S, Michel FJ, Wevrick R, Zechner U, Swaab D, Dudley K, Bezin L, Muscatelli F

PLoS genetics - Jan 2013

A single postnatal injection of oxytocin rescues the lethal feeding behaviour in mouse newborns deficient for the imprinted Magel2 gene.

Schaller F, Watrin F, Sturny R, Massacrier A, Szepetowski P, Muscatelli F

Human molecular genetics - Dec 2010

Inactivation of Socs3 in the hypothalamus enhances the hindbrain response to endogenous satiety signals via oxytocin signaling.

Matarazzo V, Schaller F, Nédélec E, Benani A, Pénicaud L, Muscatelli F, Moyse E, Bauer S

The Journal of neuroscience : the official journal of the Society for Neuroscience - Nov 2012

Respiratory sympathetic modulation is augmented in chronic kidney disease.

Saha M, Menuet C, Sun QJ, Burke PGR, Hildreth CM, Allen AM, Phillips JK

Respiratory physiology & neurobiology - Apr 2019

Mapping and Analysis of the Connectome of Sympathetic Premotor Neurons in the Rostral Ventrolateral Medulla of the Rat Using a Volumetric Brain Atlas.

Dempsey B, Le S, Turner A, Bokiniec P, Ramadas R, Bjaalie JG, Menuet C, Neve R, Allen AM, Goodchild AK, McMullan S

Frontiers in neural circuits - Jan 2017

Polycythemia and high levels of erythropoietin in blood and brain blunt the hypercapnic ventilatory response in adult mice.

Menuet C, Khemiri H, de la Poëze d'Harambure T, Gestreau C

American journal of physiology. Regulatory, integrative and comparative physiology - May 2016

Respiratory modulation of sympathetic nerve activity is enhanced in male rat offspring following uteroplacental insufficiency.

Menuet C, Wlodek ME, Fong AY, Allen AM

Respiratory physiology & neurobiology - Jun 2016

Catecholaminergic C3 neurons are sympathoexcitatory and involved in glucose homeostasis.

Menuet C, Sevigny CP, Connelly AA, Bassi JK, Jancovski N, Williams DA, Anderson CR, Llewellyn-Smith IJ, Fong AY, Allen AM

The Journal of neuroscience : the official journal of the Society for Neuroscience - Nov 2014

Angiotensin type 1A receptor expression in C1 neurons of the rostral ventrolateral medulla contributes to the development of angiotensin-dependent hypertension.

Jancovski N, Carter DA, Connelly AA, Stevens E, Bassi JK, Menuet C, Allen AM

Experimental physiology - Dec 2014

Baroreceptor reflex control of heart rate in angiotensin type 1A receptor knockout mice.

Choong YT, Menuet C, Jancovski N, Allen AM

Physiological reports - Nov 2013

Stimulation of angiotensin type 1A receptors on catecholaminergic cells contributes to angiotensin-dependent hypertension.

Jancovski N, Bassi JK, Carter DA, Choong YT, Connelly A, Nguyen TP, Chen D, Lukoshkova EV, Menuet C, Head GA, Allen AM

Hypertension (Dallas, Tex. : 1979) - Nov 2013

Increasing brain protein O-GlcNAc-ylation mitigates breathing defects and mortality of Tau.P301L mice.

Borghgraef P, Menuet C, Theunis C, Louis JV, Devijver H, Maurin H, Smet-Nocca C, Lippens G, Hilaire G, Gijsen H, Moechars D, Van Leuven F

PloS one - Jan 2013

[Electrophysiological, molecular and genetic identifications of the pre-Bötzinger complex].

Viemari JC, Menuet C, Hilaire G

Medecine sciences : M/S - Oct 2013

The H3K27 demethylase JMJD3 is required for maintenance of the embryonic respiratory neuronal network, neonatal breathing, and survival.

Burgold T, Voituron N, Caganova M, Tripathi PP, Menuet C, Tusi BK, Spreafico F, Bévengut M, Gestreau C, Buontempo S, Simeone A, Kruidenier L, Natoli G, Casola S, Hilaire G, Testa G

Cell reports - Nov 2012

Isoflurane anesthesia precipitates tauopathy and upper airways dysfunction in pre-symptomatic Tau.P301L mice: possible implication for neurodegenerative diseases.

Menuet C, Borghgraef P, Voituron N, Gestreau C, Gielis L, Devijver H, Dutschmann M, Van Leuven F, Hilaire G

Neurobiology of disease - Apr 2012
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