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Wnt signaling regulates neuronal migration and differentiation in the cerebral cortex

English title Wnt signaling regulates neuronal migration and differentiation in the cerebral cortex
Applicant Kiss Jozsef Zoltan
Number 159795
Funding scheme Project funding (Div. I-III)
Research institution Dépt des Neurosciences Fondamentales Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Neurophysiology and Brain Research
Start/End 01.05.2015 - 30.04.2018
Approved amount 372'000.00
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Keywords (6)

Wnt signaling; layer II pyramidal neurons; development; in utero electroporation; video time-lapse microscopy; cell migration

Lay Summary (French)

Lead
Le développement du cerveau et de ses circuits neuronaux nécessite une orchestration minutieuse des évènements qui contrôlent la position, l’orientation et la connexion des neurones entre eux. Toute anomalie de migration résulte en des maladies du développement cérébral plus ou moins sévères.
Lay summary

Les voies de signalisation provenant des protéines de la famille Wnt sont impliquées dans des pathologies neurologiques et psychiatriques qui résultent de la migration défectueuse des neurones. Cependant, le rôle direct des signaux Wnt dans la migration neuronale n’a pas été établi.

Nous avons montré qu’en contrôlant l’activité de la voie de signalisation canonique Wnt/ß-catenin pendant certaines phases critiques du développement cérébral, il est possible de modifier la migration et la polarisation des neurones pyramidaux. Mais quels sont les mécanismes et la spécificité de la voie canonique Wnt dans cette régulation de migration?

Nous avons trouvé que les voies canonique et non-canonique de signalisation Wnt sont toutes deux actives dans les cellules qui migrent radialement. De plus, nous avons montré que le ligand non-canonique le mieux connu, Wnt5a, est exprimé par les précurseurs des cellules pyramidales.

Notre hypothèse est donc que les voies canonique et non-canonique de signalisation Wnt agissent de conserve dans ces cellules pour réguler leur polarisation, leur migration, ainsi que les stades précoces de leur différenciation. Nous proposons de tester cette hypothèse dans les cerveaux de rats, en particulier dans le développement des cellules pyramidales de la couche II.

Le travail que nous proposons ici devrait permettre de mieux comprendre comment les phases clefs de la migration et de la différenciation des cellules pyramidales sont contrôlées par une activité coordonnée des voies canonique et non-canonique de signalisation Wnt.

Conséquemment, notre travail pourra mettre en perspective les liens entre une dé-régulation des voies de signalisation Wnt et certaines maladies du développement cérébral.

 

Direct link to Lay Summary Last update: 28.04.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Electrophysiological Evidence for the Development of a Self-Sustained Large-Scale Epileptic Network in the Kainate Mouse Model of Temporal Lobe Epilepsy
Sheybani Laurent, Birot Gwenaël, Contestabile Alessandro, Seeck Margitta, Kiss Jozsef Zoltan, Schaller Karl, Michel Christoph M., Quairiaux Charles (2018), Electrophysiological Evidence for the Development of a Self-Sustained Large-Scale Epileptic Network in the Kainate Mouse Model of Temporal Lobe Epilepsy, in The Journal of Neuroscience, 38(15), 3776-3791.
Multimodal MRI Imaging of Apoptosis-Triggered Microstructural Alterations in the Postnatal Cerebral Cortex
Petrenko Volodymyr, van de Looij Yohan, Mihhailova Jevgenia, Salmon Patrick, Hüppi Petra S, Sizonenko Stéphane V, Kiss Jozsef Z (2018), Multimodal MRI Imaging of Apoptosis-Triggered Microstructural Alterations in the Postnatal Cerebral Cortex, in Cerebral Cortex, 28(3), 949-962.
Perturbed Wnt signaling leads to neuronal migration delay, altered interhemispheric connections and impaired social behavior
Bocchi Riccardo, Egervari Kristof, Carol-Perdiguer Laura, Viale Beatrice, Quairiaux Charles, De Roo Mathias, Boitard Michael, Oskouie Suzanne, Salmon Patrick, Kiss Jozsef Z. (2017), Perturbed Wnt signaling leads to neuronal migration delay, altered interhemispheric connections and impaired social behavior, in Nature Communications, 8(1), 1158-1158.
EMMPRIN overexpression in SVZ neural progenitor cells increases their migration towards ischemic cortex
Kanemitsu Michiko, Tsupykov Oleg, Potter Gaël, Boitard Michael, Salmon Patrick, Zgraggen Eloisa, Gascon Eduardo, Skibo Galina, Dayer Alexandre G., Kiss Jozsef Z. (2017), EMMPRIN overexpression in SVZ neural progenitor cells increases their migration towards ischemic cortex, in Experimental Neurology, 297, 14-24.
Relationship of Grafted FGF-2-Overexpressing Neural Stem/Progenitor Cells with the Vasculature in the Cerebral Cortex
Tsupykov Oleg, Kanemitsu Michiko, Smozhanik Ekaterina, Skibo Galina, Dayer Alexandre G., Kiss Jozsef Z. (2016), Relationship of Grafted FGF-2-Overexpressing Neural Stem/Progenitor Cells with the Vasculature in the Cerebral Cortex, in Cell Transplantation, 25(7), 1359-1369.
Astrocytes spatially restrict VEGF signaling by polarized secretion and incorporation of VEGF into the actively assembling extracellular matrixSecretion and Function of VEGF in Astrocytes
Egervari Kristof, Potter Gael, Guzman-Hernandez Maria Luisa, Salmon Patrick, Soto-Ribeiro Martinho, Kastberger Birgit, Balla Tamas, Wehrle-Haller Bernhard, Kiss Jozsef Zoltan (2016), Astrocytes spatially restrict VEGF signaling by polarized secretion and incorporation of VEGF into the actively assembling extracellular matrixSecretion and Function of VEGF in Astrocytes, in Glia, 64(3), 440-456.

Collaboration

Group / person Country
Types of collaboration
Dr. Bernhard Wehrle-Haller, Cell Physiology & Metabolism Centre Medical Universitaire/University of Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Dr. Geneviève Rougon, CNRS, Institut de Biologie du Développement de Marseille-Luminy (IBDML), France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Christoph M. Michel, ?Functional Brain Mapping Laboratory?Neurology Clinic, University Hospita Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Dominique Muller, Dépt. Neurosciences, Centre Médical Universitaire, Geneva, Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
- Exchange of personnel
Dr. Eva Mezey, NIH Bethesda, USA United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Petra S Hüppi, Service du Développement et de la Croissance, Dépt. de l'Enfant et de l'Adolesc Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Associated projects

Number Title Start Funding scheme
140940 Postnatal positioning of neuronal precursors in the medial limbic cortex: the role of WNT signaling pathways 01.05.2012 Project funding (Div. I-III)

Abstract

The proper development of cortical circuits requires highly orchestrated cell migratory events to establish specific laminar position, orientation and connectivity of neurons. Migration errors can lead to neurodevelopmental disorders including heterotopia, lissencephaly and focal cortical dysgenesis. Wnt signal transduction pathways have been implicated in psychiatric and neurological pathologies that have been associated with neuronal migration disorders. While it has been speculated that Wnt signaling might control neuronal migration, its direct role remained to be established. During the last funding period we have demonstrated that dynamically regulated activity states of canonical Wnt/ß-catenin signaling during specific migratory phases are crucial for proper polarization and migration of late generated pyramidal neurons (Boitard et al., 2014, under revision). But, how specific Wnt signaling levels are established and the mechanisms by which canonical Wnt signaling regulates migratory events remain unknown. In preliminary experiments we found that Wnt non-canonical signaling just as the ß-catenin-dependent canonical signaling transduction is active in radially migrating cells. Moreover, we show that the best characterized non-canonical ligand, Wnt5a is expressed in pyramidal precursor cells. Our preliminary experiments also suggest that there might be a crosstalk between autocrine Wnt5a/non-canonical signaling and the canonical pathway.Hypothesis: Wnt canonical and non-canonical signaling pathways cooperate in migrating pyramidal precursors to regulate cell polarization, migration and early differentiation events. Aims: We will test this hypothesis focusing on rat layer II pyramidal cells at different developmental stages including: 1) the multipolar to bipolar transition in the upper subventricular zone; 2) transitions at the level cortical plate and radial glia guided locomotion; and 3) early dendritic development including dendritic branching and spine formation. In order to test specific hypotheses concerning the role of Wnt signaling pathways in these events, we propose to electroporate doxycycline inducible constructs in utero to carry out loss-of-function or gain-of-function experiments with delayed activation. We will investigate the effects of manipulating Wnt signaling on polarization, migration and early differentiation of pyramidal cells using confocal microscopy. In order to monitor in real time the migration of neurons, video time-lapse imaging will be performed on slice preparations. Intracellular iontophoretic injection of Lucifer Yellow will be performed to achieve complete filling of apical and basal dendrites with dendritic spines. Reconstruction of three-dimensional dendritic structures will be carried out on a computer-based Neurolucida system.Significance: The work proposed here may uncover how the coordinated activity of canonical and non-canonical signaling cascades control key migratory and differentiation events of pyramidal cells. Our results hold promise for understanding the mechanisms by which deregulation of Wnt signaling pathways could impact on postmitotic neurons thereby potentially underlying neurodevelopmental disorders.
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