Tissue-Type Plasminogen Activator Controlled Corticogenesis Through a Mechanism Dependent of NMDA Receptors Expressed on Radial Glial Cells

Abstract

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.

How Do Electric Fields Coordinate Neuronal Migration and Maturation in the Developing Cortex?

“…Luhmann et al (2015) review a series of studies on cell-typespecific NR1 knockouts (one good example is Iwasato et al, 2000), which indicate either the existence of compensatory mechanisms or extrinsic regulation of migration by nonneuronal target structures, like glial cells. One recent study supports the latter (Pasquet et al, 2019). Here, the authors demonstrate that proper layering of radially migrating neurons relies on NR1 clustering in radial glia fibers at contact sites with the soma and leading process of bipolar neurons (Figure 2).…”

“…MZ, marginal zone; CP, cortical plate; SP, subplate; IZ, intermediate zone; VZ, ventricular progenitors zone. Major references Hurni et al (2017) , Mayer et al (2019) , and Pasquet et al (2019) .…”

Low Density Receptor-Related Protein 1 Interactions With the Extracellular Matrix: More Than Meets the Eye

“…Recently, tPA has been implicated in the control of proper radial glial cell organization and differentiation. The interaction between neuronal tPA and NMDAR on radial glia cells was found to be crucial for proper cortical migration and maturation (Pasquet et al, 2018). In a mouse model of Fragile X syndrome, a stimulating effect of tPA on Fmr1-deficient cells migrating out of neurospheres was also apparent (Achuta et al, 2014).…”

Post-synaptic Release of the Neuronal Tissue-Type Plasminogen Activator (tPA)

“…In addition to its roles in the vascular system, tPA plays crucial functions in the central nervous system (CNS) acting either as an enzyme or as a growth-factor-like molecule (Thiebaut et al, 2018). Thus, tPA is involved in several physiological and pathological CNS processes, including corticogenesis, neuronal survival, learning and memory, anxiety, epilepsy, stroke and Alzheimer's disease (Qian et al, 1993; Baranes et al, 1998; Madani et al, 1999; Pawlak et al, 2003; Alvarez et al, 2013; Oh et al, 2014; Hébert et al, 2017; Pasquet et al, 2018). Its neuronal functions are achieved through plasminogen-dependent or plasminogen-independent effects (Melchor and Strickland, 2005).…”