A glial origin for periventricular nodular heterotopia caused by impaired expression of Filamin-A

Abstract

Periventricular nodular heterotopia (PH) is a human brain malformation caused by defective neuronal migration that results in ectopic neuronal nodules lining the lateral ventricles beneath a normal appearing cortex. Most affected patients have seizures and their cognitive level varies from normal to severely impaired. Mutations in the Filamin-A (or FLNA) gene are the main cause of PH, but the underlying pathological mechanism remains unknown. Although two FlnA knockout mouse strains have been generated, none of them showed the presence of ectopic nodules. To recapitulate the loss of FlnA function in the developing rat brain, we used an in utero RNA interference-mediated knockdown approach and successfully reproduced a PH phenotype in rats comparable with that observed in human patients. In FlnA-knockdown rats, we report that PH results from a disruption of the polarized radial glial scaffold in the ventricular zone altering progression of neural progenitors through the cell cycle and impairing migration of neurons into the cortical plate. Similar alterations of radial glia are observed in human PH brains of a 35-week fetus and a 3-month-old child, harboring distinct FLNA mutations not previously reported. Finally, juvenile FlnA-knockdown rats are highly susceptible to seizures, confirming the reliability of this novel animal model of PH. Our findings suggest that the disorganization of radial glia is the leading cause of PH pathogenesis associated with FLNA mutations. Rattus norvegicus FlnA mRNA (GenBank accession number FJ416060).

Replication of early and recent Zika virus isolates throughout mouse brain development

“…The morphology of the RGP basal processes was impaired with ZIKV infection, which no longer provided a linear scaffold for migration of neuronal precursors. A similar scaffold disorganization was observed in ZIKV-infected organotypic human fetal brain slices (42) and is an important contributor to other neurodevelopmental diseases (43). It is unclear if the disarray of the RGP basal processes led to the neuronal migration abnormalities found in ZIKV-infected slices, and/or if other mechanisms such as increased apoptosis or changes intrinsic to the migrating neuronal precursors led to their impaired migration.…”

TBC1D24 regulates neuronal migration and maturation through modulation of the ARF6-dependent pathway

“…Breeding and experimental procedures were carried out in accordance with European and the local ethical committee guidelines for animal research. IUE and neuronal migration analysis were performed as described previously (35). For more details, see SI Materials and Methods.…”

WNK1-regulated inhibitory phosphorylation of the KCC2 cotransporter maintains the depolarizing action of GABA in immature neurons

“…In utero injections and electroporations were performed as previously described (70) in embryos from timed pregnant rats (embryonic day 15) that were anesthetized with ketamine (100 mg/kg; IMALGENE 1000, Merial)/xylazine (10 mg/kg; Rompun 2%, Bayer Healthcare). Wistar rats (Janvier) were raised and mated at INMED (Institut de Neurobiologie de la Méditerranée) Post-Genomic Platform animal facility in agreement with the European Union and French legislations.…”