title: Disruption of neural progenitors along the ventricular and subventricular zones in periventricular heterotopia.
abstract: Periventricular heterotopia (PH) is a disorder characterized by neuronal nodules, ectopically positioned along the lateral ventricles of the cerebral cortex. Mutations in either of two human genes, Filamin A (FLNA) or ADP-ribosylation factor guanine exchange factor 2 (ARFGEF2), cause PH (Fox et al. in 'Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia'. Neuron, 21, 1315-1325, 1998; Sheen et al. in 'Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex'. Nat. Genet., 36, 69-76, 2004). Recent studies have shown that mutations in mitogen-activated protein kinase kinase kinase-4 (Mekk4), an indirect interactor with FlnA, also lead to periventricular nodule formation in mice (Sarkisian et al. in 'MEKK4 signaling regulates filamin expression and neuronal migration'. Neuron, 52, 789-801, 2006). Here we show that neurons in post-mortem human PH brains migrated appropriately into the cortex, that periventricular nodules were primarily composed of later-born neurons, and that the neuroependyma was disrupted in all PH cases. As studied in the mouse, loss of FlnA or Big2 function in neural precursors impaired neuronal migration from the germinal zone, disrupted cell adhesion and compromised neuroepithelial integrity. Finally, the hydrocephalus with hop gait (hyh) mouse, which harbors a mutation in Napa [encoding N-ethylmaleimide-sensitive factor attachment protein alpha (alpha-SNAP)], also develops a progressive denudation of the neuroepithelium, leading to periventricular nodule formation. Previous studies have shown that Arfgef2 and Napa direct vesicle trafficking and fusion, whereas FlnA associates dynamically with the Golgi membranes during budding and trafficking of transport vesicles. Our current findings suggest that PH formation arises from a final common pathway involving disruption of vesicle trafficking, leading to impaired cell adhesion and loss of neuroependymal integrity.
authors.affiliation: Department of Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Ferland
authors.forename: Luis Federico
authors.initials: LF
authors.lastname: Batiz
authors.forename: Jason
authors.initials: J
authors.lastname: Neal
authors.forename: Gewei
authors.initials: G
authors.lastname: Lian
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bundock
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Hsiao
authors.forename: Rachel
authors.initials: R
authors.lastname: Diamond
authors.forename: Davide
authors.initials: D
authors.lastname: Mei
authors.forename: Alison H
authors.initials: AH
authors.lastname: Banham
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Brown
authors.forename: Charles R
authors.initials: CR
authors.lastname: Vanderburg
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Joseph
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Hecht
authors.forename: Rebecca
authors.initials: R
authors.lastname: Folkerth
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
authors.forename: Esteban M
authors.initials: EM
authors.lastname: Rodriguez
authors.forename: Volney L
authors.initials: VL
authors.lastname: Sheen
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D002552:Cerebral Ventricles / Q000166:cytology* / Q000503:physiopathology; D003285:Contractile Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D064448:Filamins; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D054091:Periventricular Nodular Heterotopia / Q000473:pathology* / Q000503:physiopathology; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology*
chemical_list: C119088:ARFGEF2 protein, human; D003285:Contractile Proteins; D064448:Filamins; D020662:Guanine Nucleotide Exchange Factors; D008840:Microfilament Proteins; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins