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Cerebral malformations in the HeCo mouse and human cases linked to altered neural progenitors proliferation and differentiation and delayed migration of post-mitotic neurons through a common microtubule complex dysfunction.

English title Cerebral malformations in the HeCo mouse and human cases linked to altered neural progenitors proliferation and differentiation and delayed migration of post-mitotic neurons through a common microtubule complex dysfunction.
Applicant Croquelois Alexandre
Number 135574
Funding scheme Project funding (Div. I-III)
Research institution Service de Rhumatologie, Médecine Physique et Réhabilitation Hôpital Nestlé - CHUV
Institution of higher education University of Lausanne - LA
Main discipline Neurophysiology and Brain Research
Start/End 01.06.2011 - 31.05.2014
Approved amount 152'434.00
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All Disciplines (2)

Discipline
Neurophysiology and Brain Research
Embryology, Developmental Biology

Keywords (8)

Cerebral Cortex; Neuronal Migration Disorders; Epilepsy; Models, Animal; Mental Retardation; Development; Mice; Microtubule

Lay Summary (English)

Lead
Lay summary

Background

In humans, cortical malformations are commonly associated with developmental delays, mental retardation and epilepsy. Available animal models are few and this represents a major limit in understanding precise mechanisms of abnormal cortical development and lowered epileptic threshold. A new autosomal recessive mouse model of cortical heterotopia (HeCo), that appeared spontaneously in the colony and shares some of the characteristics of the corresponding human disorder (developmental delay, increased tendency to epileptic seizures) was discovered in the applicant’s laboratory. The genetic origin has been elucidated and there is strong evidence that a little studied microtubule associated protein (MAP) mutation is responsible for the phenotype. The screening of human cases revealed that mutations of the otholog gene in humans produce severe brain malformations.

 

Hypotheses

The cortical malformation in mice and humans is due to abnormal migration and/or proliferation patterns.

Neural progenitors are abnormally located in the developing cerebral cortex.

Abnormal migration and proliferation patterns and abnormal neural progenitors location are due to a dysfunction of the microtubule cytoskeleton.

 

Methods

Different neural progenitors and proliferation markers will be used to determine the position of the different progenitor populations.

Ex-vivo and in-utero electroporation of different plasmids in both mutant and control mice will be used to determine the migration pattern of post-mitotic neurons (speed, direction).

 

Expected results

These studies will identify a new heterotopia gene and pinpoint a novel biochemical pathway critical for cortical development. It will also highlight the little-studied theme of the involvement of ectopic proliferation in the pathophysiology of subcortical heterotopia.

The mouse mutant HeCo allowed to discover a new gene involved in cortical development that is also responsible for human cerebral malformations. It is a rare model to study cortical development but also epilepsy. It represents a good example of translational medicine and therefore could permit to better understand human cases and refine anti-epileptic treatments. Finally, as it has been often demonstrated in the past, the discovery of a new gene could also be a tool for researches outside the scope of the present project.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
[Mutations in Eml1/EML1 lead to ectopic progenitors and neuronal heterotopia in mouse and human].
Kielar Michel, Phan Dinh Tuy Françoise, Bizzotto Sara, Belvindrah Richard, Croquelois Alexandre, Francis Fiona (2014), [Mutations in Eml1/EML1 lead to ectopic progenitors and neuronal heterotopia in mouse and human]., in Médecine sciences : M/S, 30(12), 1087-90.
Mutations in Eml1 lead to ectopic progenitors and neuronal heterotopia in mouse and human.
Kielar Michel, Tuy Françoise Phan Dinh, Bizzotto Sara, Lebrand Cécile, de Juan Romero Camino, Poirier Karine, Oegema Renske, Mancini Grazia Maria, Bahi-Buisson Nadia, Olaso Robert, Le Moing Anne-Gaëlle, Boutourlinsky Katia, Boucher Dominique, Carpentier Wassila, Berquin Patrick, Deleuze Jean-François, Belvindrah Richard, Borrell Victor, Welker Egbert, Chelly Jamel, Croquelois Alexandre, Francis Fiona (2014), Mutations in Eml1 lead to ectopic progenitors and neuronal heterotopia in mouse and human., in Nature neuroscience, 17(7), 923-33.

Collaboration

Group / person Country
Types of collaboration
Prof. Jamel Chelly, Institut Cochin, Paris France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr Fiona Francis, Institut du Fer-à-Moulin, Université Pierre et Marie Curie, Paris France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Jean-Pierre Hornung Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Associated projects

Number Title Start Funding scheme
124089 Imaging large scale neuronal networks in epilepsy 01.05.2009 SPUM

Abstract

SummaryIn humans, cortical malformations are commonly associated with developmental delays, mental retardation and epilepsy. Available animal models are few and this represents a major limit in understanding precise mechanisms of abnormal cortical development and lowered epileptic threshold. A new autosomal recessive mouse model of cortical heterotopia (HeCo), that appeared spontaneously in the colony and shares some of the characteristics of the corresponding human disorder (developmental delay, increased tendency to epileptic seizures) was discovered in the applicant’s laboratory. The genetic origin has been elucidated and there is strong evidence that a little studied microtubule associated protein (MAP) mutation is responsible for the phenotype. The screening of human cases revealed that mutations of the corresponding gene in humans produce severe brain malformations. Cortical heterotopias could be due to abnormal migration of post-mitotic neurons, but also to altered proliferation, differentiation and migration of neural progenitors and to altered programmed cell death. Finally, as some of the developmental neural mechanisms could be still present in adults (neurogenesis in the hippocampus), a mutation of a developmental protein could also have effects in adults.Therefore, the aims of the present project are :1. To confirm that the gene mutation is responsible for the HeCo phenotype?2. To study the neural progenitors and their proliferation, differentiation and location in HeCo mice?3. To study the programmed cell death in the HeCo phenotype4. To determine post-mitotic neurons migration pattern in HeCo mice5. To study the adult neurogenesis in the mouse mutant HeCoThe methods used in the present application are:1. Ex-vivo and in-utero electroporation of different plasmids (GFP, Rescued gene, siRNA)2. Immuno-labeling for specific markers of neural progenitors, post-mitotic neurons and astrocytes.3. Deoxynucleotidyl transferase (TdT)-mediated dUTP nick endlabeling (TUNEL) reaction to determine programmed cell death.4. Confocal Time-Lapse Microscopy to determine neuronal migration pattern.5. A virus-based gene delivery approach to express the green fluorescent protein (GFP) in adult-born neuronsFirst results strongly suggest that the discovered gene is responsible for the HeCo phenotype and human cases, unless this has to be confirmed by the proposed experiments. We expect that gene rescuing will restore, at least partially, a normal phenotype in HeCo mice. In the same way, the siRNA experiments should demonstrate a cortical dysembryogenesis in control animals. We also demonstrated that the HeCo phenotype is linked to an abnormal proliferation within the intermediate zone and the role of neural progenitors has to be confirmed. We also expect that the post-mitotic neurons migration pattern will be altered in HeCo mice. Finally we will determine the role of this new gene in adult neurogenesis.This project will demonstrate the multiple mechanisms associated with this new microtubule associated protein and their role in heterotopia formation. Beside these developmental aspects, this gene could lead to a better understanding of adult neurogenesis.
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