Modifications of neuronal migration during development, including processes that control cortical lamination are associated with functional deficits at adult stage. Here, we report for the first time that the lack of the serine protease tissue-type Plasminogen Activator (tPA), previously characterized as a neuromodulator and a gliotransmitter, leads to an altered cortical lamination in adult. This results in a neuronal migration defect of tPA deficient neurons which are stopped in the intermediate zone at E16. This phenotype is rescued by re-expressing a wild-type tPA in cortical neurons at E14 but not by a tPA that cannot interact with NMDAR. We thus hypothetized that the tPA produced by cortical neuronal progenitors can control their own radial migration through a mechanism dependent of NMDAR expressed at the surface of radial glial cells (RGC). Accordingly, conditional deletion of tPA in neuronal progenitors at E14 or overexpression of a dominant-negative NMDAR that cannot bind tPA in RGC also delayed neuronal migration. Moreover, the lack of tPA lead to an impaired maturation and orientation of RGC. These data provide the first demonstration that the neuronal serine protease tPA is an actor of a proper corticogenesis by its ability to control NMDAR signaling in RGC.
Keywords: NMDA receptor; corticogenesis; radial glial cells; tissue-type plasminogen activator.
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