Ferland R, Batiz L, Neal J, et al.. Disruption of neural progenitors along the ventricular and subventricular zones in periventricular heterotopia. Hum Mol Genet.18(3):497-516

Department of Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
Human Molecular Genetics (Impact Factor: 6.39). 12/2008; 18(3):497-516. DOI: 10.1093/hmg/ddn377
Source: PubMed


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.

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Article: Ferland R, Batiz L, Neal J, et al.. Disruption of neural progenitors along the ventricular and subventricular zones in periventricular heterotopia. Hum Mol Genet.18(3):497-516

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    • "Mutations in the Arf1 GEF BIG2 have been linked to autosomal recessive periventricular heterotopia (ARPH), a disorder that leads to severe malformation of the cerebral cortex (Sheen et al., 2004). Disease symptoms are a result of the failure of a specific class of neurons to migrate from their point of origin to the cerebral cortex, due to a defect in the adhesion properties of these neurons (Ferland et al., 2009; Sheen et al., 2004). The IQSEC/BRAG Arf GEFs are highly expressed in the postsynaptic density of the central nervous system (Casanova, 2007), and play important roles in signaling during synaptic transmission (Myers et al., 2012). "
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    • "This not only allows specific neuronal subpopulations to be identified on the basis of their expression profiles, but also provides information concerning their birth dates and migration [13,14]. Over the last few years, a number of studies have used LSGs to investigate cortical development under normal and pathological conditions in animal models [15-18] and humans [19-25]. "
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    • "It seems the most likely explanation for the development of seizure disorder in hydrocephalic patients is the presence of associated malformations (PH?) in the cerebral cortex. Evidence indicating that PH may result from radial glial/NSCs fiber disruption during embryonic development has been reported [10-12,21,32]. "
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