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2014

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Study of KIF2A mutant models : new insights into brain development and cortical malformations-related epilepsy.

Research unit

UMR 7104 - Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)
1 rue Laurent Fries 67404 ILLKIRCH

Group

Name: Génétique et Pathophysiologie de maladies épileptogènes développementales

Group leader: CHELLY Jamel - jamel.chelly@inserm.fr

Group leader's phone: 0144412410

Website: Visit website

Group organization:
- Chercheurs: 6
- ITA: 3
- Doctorants: 3
- Post-Docs: 1
- Autres: 2

Publications of the team linked to the topic (3 last years):
1) Nadia Bahi-Buisson N, Poirier K, Fourniol F, Saillour Y, Valence S, Lebrun N, Hully M, Fallet Bianco C, Boddaert N, Elie C, Lascelles K, Souville I, LIS-Tubulinopathies consortium, Beldjord C, Chelly J. The wide spectrum of Tubulinopathies: what are the key features for the diagnosis?. Brain, 2014 ; in press
2) Saillour Y, Broix L, Bruel-Jungerman E, Lebrun N, Muraca G, Rucci J, Poirier K, Belvindrah R, Francis F, Chelly J. Beta tubulin isoforms are not interchangeable for rescuing impaired radial migration due to Tubb3 knockdown. Hum Mol Genet. 2013 [Epub ahead of print].
3) Poirier K, Lebrun N, Broix L, Tian G, Saillour Y, Boscheron C, Parrini E, Valence S, Pierre BS, Oger M, Lacombe D, Geneviève D, Fontana E, Darra F, Cances C, Barth M, Bonneau D, Bernadina BD, N'guyen S, Gitiaux C, Parent P, des Portes V, Pedespan JM, Legrez V, Castelnau-Ptakine L, Nitschke P, Hieu T, Masson C, Zelenika D, Andrieux A, Francis F, Guerrini R, Cowan NJ, Bahi-Buisson N, Chelly J. Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly. Nat Genet. 2013 Jun;45(6):639-47.

About PhD

PhD Director: CHELLY Jamel - jamel.chelly@inserm.fr

Phone: 0144412410

Junior advisor: non

Co-tutely: non

Co-Director: non

About PhD topic :

Title: Study of KIF2A mutant models : new insights into brain development and cortical malformations-related epilepsy.

Project: About 0.5-1% of the population has epilepsy and more than 50% of patients develop their first seizure in childhood. Epileptogenic developmental disorders (EDD) are now, mostly thought, to be related to disruption of genetic programs required for the coordinated timing of cortical development. Among EDD, malformations of cortical development (MCDs), focal cortical dysplasias (FCD) and epileptic encephalopathy (EEs) are frequent causes of severe epilepsies and intellectual deficits (Barkovich et al., Brain 2012;135:1348-69) and represent therefore serious medical issue.

Our group has significantly contributed in the progress regarding genetics of EE and MCD. For instance, we recently showed that dysfunction of proteins such as TUBG1, DYNC1H1, KIF5C and KIF2A underlies a large spectrum of MCD (Poirier et al., Nat Genet 2013;45:639-47).

In this project, we propose to focus on the cellular and neurodevelopmental consequences resulting from KIF2A dysfunction involved in MCD. KIF2A is a member of the kinesin-13 family and regulates MT dynamics of the microtubules(MT) by depolymerizing them. Using in utero electroporation approach, we showed that KIF2A mutations causing-disease cause a significant arrest of migrating neurons, and affect cell proliferation.

The proposed thesis is in continuation with the findings mentioned above and the main objective will be to better understand biological processes of the mecanisms involved in the pathogenesis of cortical malformations resulting from mutations in KIF2A gene. The first part of this project will be to explore whether the process of neuronal migration could be re-initiated in neurons stalled in the deepest cortical layers by the overexpressing wild type (WT) KIF2A. In other words, is that arrest of neuronal cells is reversible? Is there a developmental time window during which neuronal cells keep a potential of migration, as shown for Dcx models (Manent et al., Nat Med 2009;15:84-90)? To achieve this goal, two complementary strategies using appropriate tools will be explored. The first strategy will consist in the reexpression of inducible WT KIF2A at different postnatal days in the blocked neurons overexpressing mutants KIF2A. In contrast, the second strategy will consist in switching off KIF2A mutants expression after birth. Thus, in both cases one could assess neurons potential to restart the migration process.

To complete and strengthen our findings, we will also generate (through ongoing collaboration with ICS) knock-in mouse model bearing one of the mutated form of KIF2A (i.e., c.961C>G, p.His321Asp) found in patients with MCD. We will use mutant mouse model to study brain brain development, laminar organization, cytoarchitecture, migration, progenitor proliferation and axonal tracts, as well consequences on MTs-related biological processes such as cellular trafficking. This model will also be explored at the phenotypic level, including motor and behavioral performances, memory abilities, and susceptibility to seizures. In case where neuroanatomical and histological investigations would reveal neuronal migration defects correlated with phenotypic symptoms we will attempt to rescue the cellular phenotype (ie. migration defect) by overexpressing WT kif2a using in utero electroporation strategy and assess how (and when) re-initiation of neuronal migration might occur. In addition to its potential to generate animal model for epilepsy; this research project will provide new insights for the understanding of KIF2A-related MCD and open perspective for neuronal migration manipulation.

Feasibility and development of this proposed project will benefit from the experience of the group in genetics and pathophysiology of neuro-developmental disorders, as well as the scientific environmental and facilities offered by the exceptional scientific and state of the art equipment and common platforms of the IGBMC.

Wished skills: -Molecular engineering
-cell biology and cell processes involving microtubules
-neurobiology-neurodevelopment- pathophysiology of cortical development diseases

Expertises which will be acquired during the training: In utero electroporation- animal experiment- molecular cloning- cell imaging and videomicroscopy- approaches and explorations of cortical and cerebral development.