Human Molecular Genetics Advance Access originally published online on November 7, 2008
Human Molecular Genetics 2009 18(3):497-516; doi:10.1093/hmg/ddn377
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Disruption of neural progenitors along the ventricular and subventricular zones in periventricular heterotopia
1 Department of Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA 2 The Wadsworth Center, Albany, NY 12201, USA 3 Instituto de Anatomía, Histología y Patología, Universidad Austral de Chile, Valdivia, Chile 4 Department of Neurology 5 Department of Neuropathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA 6 Department of Neuropathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA 7 Advanced Tissue Resource Center, Center for Molecular Pathology, Harvard Center for Neurodegeneration and Repair, Massachusetts General Hospital, Boston, MA 02114, USA 8 Department of Child Neurology and Psychiatry, University of Pisa and IRCCS Fondazione Stella Maris 56018, Calambrone, Pisa, Italy 9 Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Level 4 Academic Block, John Radcliffe Hospital, Oxford, Oxfordshire OX3 9DU, UK 10 Howard Hughes Medical Institute and Division of Genetics, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
* To whom correspondence should be addressed. Tel: +1 6176674078; Fax: +1 6176677919; E-mail: vsheen{at}bidmc.harvard.edu
Received October 13, 2008; Accepted November 5, 2008
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 (
-SNAP)], also develops a progressive denudation of the neuroepithelium, leading to periventicular 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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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