Team 4

Genetics and neurodevelopment

Director : Judith MELKI, PU-PH, APHP
Deputy Director : Marcel TAWK, CRCN, INSERM

Researches Team 4

The Melki’s and Tawk’s groups have developed a close and fruitful collaboration over the last few years in order to gain insight into several aspects of neurodevelopment including the neuromuscular system, myelination, neuronal development and cerebral vasculature. We are interested in understanding the molecular mechanism and genetic basis of early onset neuromuscular disorders, arthrogryposis multiplex congenita, peripheral neuropathies and congenital anomaly of the cerebral vasculature.

By combining pharmacological, genetics, molecular and cellular approaches and through patients’ recruitment and animal models’ elaboration, we aim to decipher some fundamental features of neurodevelopment and to unravel novel candidate disease mechanisms of human neuronopathies.

Staff members

ORCID Number
Melki Judithjudith.melki@inserm.frPU-PH0000-0002-9125-3171

Tawk Marcel

Echaniz-Laguna Andoniandoni.echaniz-laguna@aphp.frPU-PH0000-0003-1012-9783
Baulieu Etienne-Emileetienne.baulieu@inserm.frPU-PH0000-0002-2532-5085
Benachi Alexandraalexandra.benachi@aphp.frPU-PH0000-0001-6045-0765
Labrune Philippephilippe.labrune@aphp.frPU-PH0000-0002-0374-0544
Degerny Cindycindy.degerny@u-psud.frMCU0000-0002-9810-3627
Martinovic Jelenajelana.martinovic@aphp.frPH0000-0003-4595-7271
Cambourg Patrickpatrick.cambourg@inserm.frTN 
Guidoux-Boralevi Sylviesylvie.guidoux-boralevi@inserm.frIE0000-0003-1165-0044
Delespierre Brigittebrigitte.delespierre@inserm.frTCH0000-0003-4430-2142
Lesport Emilieemilie.lesport@inserm.frResearcher0000-0001-8078-2361
Giustiniani Julienjulien.giustiniani@inserm.frResearcher0000-0003-0373-5857
Fréchou Magaliemagalie.frechou@inserm.frResearcher0000-0001-8676-1000
Vivanti Alexandrealexandre.vivanti@inserm.frMD, PhD, CCA0000-0002-4921-0047
Jaber Danadana.jaber@inserm.frPhD student 
Mikdache Ayaaya.mikdache@inserm.frPhD student 
Dorval Alanalan.dorval@inserm.frIE, CDD 

Grants :

– PHRC (AOM10181, 2010-2014)  J Melki (principal investigator)
– Agence de Biomédecine (2014): J Melki (principal investigator)
– Agence de Biomédecine (2015) : J Melki (principal investigator)
– Agence de Biomédecine (2016) : J Melki (principal investigator)
– AFM (2013-2018) : J Melki (principal investigator)

Collaborators :

– Pr H Topaloglu, Université d’Ankara, Turquie
– Dr I Gut, CNAG, Barcelone, Espagne
– Dr JL Bessereau, INSERM U-1217, Institut NeuroMyoGe`ne, Univ Lyon, Universite´ Claude Bernard Lyon 1, CNRS UMR-5310, F-69622 Villeurbanne, France
– Dr B Reversade, Institute of Medical Biology, A*STAR, Singapore
– Dr J Devaux, UMR-7286, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Aix-Marseille Universite
– Pr NG Laing, Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, Australia

Genetics and neurodevelopment

PI : Judith Melki

Our main research is focused on deciphering the genetic basis of several fetal and infantile diseases including arthrogryposis, a heterogeneous group of fetal neuromuscular disorders diseases, peripheral neuropathies and congenital anomaly of the cerebral vasculature. To support gene discovery, our have set up a genomics facility including a server for in-house bioinformatics analysis of SNPs and data from whole or targeted exome sequencing. Functional genomics are performed using various cellular or animal models to help understand how discovered gene mutations affect phenotypes.

This approach should lead to the identification of possibly novel signaling pathways involved in the process of development and/ maintenance of the neuromuscular system, peripheral myelination and brain vasculature in human. Moreover, our approaches should open new avenue in the genetic investigation of these diseases.

Nervous system development and myelination

PI : Marcel Tawk

Our broad aim is to comprehend how the different cellular players within the nervous system interact to elaborate a functional neuronal entity. We mainly focus on the axo-glial communication, a fundamental process that orchestrates the assembly of the myelin sheath. The latter is a plasma membrane extension of specialised glial cells, Oligodendrocytes in the Central Nervous System and Schwann cells in the peripheral nervous system, that wraps around axons thereby permitting the rapid conduction of nerve impulses. Myelin disruption underlies several human diseases, such as Multiple sclerosis and Charcot-Marie-Tooth. In order to gain insight into this mechanism, we use the simplicity and high optical quality of the zebrafish embryo to monitor early and most fundamental behaviour of developing neuronal and glial cells. Some of the questions we beg: i) What are the molecular signallings that shape the peripheral myelinating glia? We have initiated a differential screen looking for genes that are dysregulated in the absence of Schwann cells using zebrafish. This screen helped us in identifying several new candidates that regulate different aspects of peripheral nervous system development. ii) How do Schwann cells migrate and divide along growing axons in order to myelinate? We use pharmacological and genetics tools, laser ablation, in vivo time-lapse imaging and transmitted electron microscopy to study the different molecular and cellular aspects that shape Schwann cell migration, division and behaviour.

Dementias and neurodegeneration : A role for FKBP52 in Tau function

PI : Étienne-Émile Baulieu

We are studying in vivo functions of the FK506 Binding Protein 52 (FKBP52) in relation to nervous system development (axonal growth, neuron viability) and its interaction with the microtubule associated protein Tau.

The pathological mutant of Tau containing a proline-to-leucine mutation at position 301 (P301L) leads to severe human tauopathy. We identified a direct interaction of FKBP52 with Tau-P301L and its phosphorylated forms and demonstrated FKBP52’s ability to induce the formation of Tau-P301L oligomers. In a transgenic zebrafish expressing the human Tau-P301L mutant, FKBP52 knockdown is sufficient to redrive defective axonal outgrowth and branching related to Tau-P301L expression in spinal primary motoneurons.