in utero electroporation; video time-lapse microscopy; development; cell migration; Wnt signaling; medial limbic cortex
Boitard Michael, Bocchi Riccardo, Egervari Kristof, Petrenko Volodymyr, Viale Beatrice, Gremaud Stéphane, Zgraggen Eloisa, Salmon Patrick, Kiss Jozsef Z (2015), Wnt signaling regulates multipolar-to-bipolar transition of migrating neurons in the cerebral cortex., in Cell reports
, 10(8), 1349-61.
Kiss Jozsef Z, Vasung Lana, Petrenko Volodymyr (2014), Process of cortical network formation and impact of early brain damage., in Current opinion in neurology
, 27(2), 133-41.
Cortical layers are generated by precisely coordinated cell migration events and the mammalian cortex is particularly susceptible to disorders of migration. Understanding the mechanisms and regulation of migratory events is therefore crucial to understand how alterations in this process might contribute to neurodevelopmental disorders. It has long been known that Wnt signaling pathways play a central role in many aspects of corticogenesis, including neural progenitor proliferation and neuronal differentiation, but its direct role in regulating cell migration and positioning remained unknown. We focuse our studies on the dorsomedial limbic cortex, comprising the cingulate and retrosplenial cortex. We propose to refine our molecular tools to target Wnt canonical signaling in order to test a series of specific hypotheses concerning the role of this signaling pathway in events including: 1) polarizing multipolar progenitors towards the cortex; 2) radial glia mediated locomotion and 3) cell positioning during the final stage of radial migration. We will engineer doxycycline inducible constructs to carry out loss-of-function or gain-of-function experiments. We plan to investigate the effects of manipulating Wnt/beta-catenin signaling on positioning and morphology 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.The work proposed here will provide novel information on the control of cell migration and positioning in the cerebral cortex. Many human neurodevelopmental disorders are associated with alterations in neuronal migration, ranging from severe malformations with mental retardation and epilepsy to disorders such as autism, schizophrenia and dyslexia. Wnt signaling pathways have been implicated in major psychiatric pathologies such as schizophrenia that are supposed to be associated with developmental disturbances. The results of these investigations may help to gain insight into the mechanisms relevant to some of these disorders