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 (α-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.

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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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    ABSTRACT: The Arf small G proteins regulate protein and lipid trafficking in eukaryotic cells through a regulated cycle of GTP binding and hydrolysis. In their GTP-bound form, Arf proteins recruit a specific set of protein effectors to the membrane surface. These effectors function in vesicle formation and tethering, non-vesicular lipid transport and cytoskeletal regulation. Beyond fundamental membrane trafficking roles, Arf proteins also regulate mitosis, plasma membrane signaling, cilary trafficking and lipid droplet function. Tight spatial and temporal regulation of the relatively small number of Arf proteins is achieved by their guanine nucleotide-exchange factors (GEFs) and GTPase-activating proteins (GAPs), which catalyze GTP binding and hydrolysis, respectively. A unifying function of Arf proteins, performed in conjunction with their regulators and effectors, is sensing, modulating and transporting the lipids that make up cellular membranes. In this Cell Science at a Glance article and the accompanying poster, we discuss the unique features of Arf small G proteins, their functions in vesicular and lipid trafficking in cells, and how these functions are modulated by their regulators, the GEFs and GAPs. We also discuss how these Arf functions are subverted by human pathogens and disease states.
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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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    ABSTRACT: Type II focal cortical dysplasias (FCDs) are malformations of cortical development characterised by the disorganisation of the normal neocortical structure and the presence of dysmorphic neurons (DNs) and balloon cells (BCs). The pathogenesis of FCDs has not yet been clearly established, although a number of histopathological patterns and molecular findings suggest that they may be due to abnormal neuronal and glial proliferation and migration processes.In order to gain further insights into cortical layering disruption and investigate the origin of DNs and BCs, we used in situ RNA hybridisation of human surgical specimens with a neuropathologically definite diagnosis of Type IIa/b FCD and a panel of layer-specific genes (LSGs) whose expression covers all cortical layers. We also used anti-phospho-S6 ribosomal protein antibody to investigate mTOR pathway hyperactivation. LSGs were expressed in both normal and abnormal cells (BCs and DNs) but their distribution was different. Normal-looking neurons, which were visibly reduced in the core of the lesion, were apparently located in the appropriate cortical laminae thus indicating a partial laminar organisation. On the contrary, DNs and BCs, labelled with anti-phospho-S6 ribosomal protein antibody, were spread throughout the cortex without any apparent rule and showed a highly variable LSG expression pattern. Moreover, LSGs did not reveal any differences between Type IIa and IIb FCD. These findings suggest the existence of hidden cortical lamination involving normal-looking neurons, which retain their ability to migrate correctly in the cortex, unlike DNs which, in addition to their morphological abnormalities and mTOR hyperactivation, show an altered migratory pattern.Taken together these data suggest that an external or environmental hit affecting selected precursor cells during the very early stages of cortical development may disrupt normal cortical development.
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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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    ABSTRACT: I was honored to be awarded the Casey Holter Essay Prize in 2013 by the Society for Research into Hydrocephalus and Spina Bifida. The purpose of the prize is to encourage original thinking in a way to improve the care of individuals with spina bifida and hydrocephalus. Having kept this purpose in mind, I have chosen the title: Neural stem cells, are they the hope of a better life for patients with fetal-onset hydrocephalus? The aim is to review and discuss some of the most recent and relevant findings regarding mechanisms leading to both hydrocephalus and abnormal neuro/gliogenesis. By looking at these outcome studies, it is hoped that we will recognize the potential use of neural stem cells in the treatment of hydrocephalus, and so prevent the disease or diminish/repair the associated brain damage.
    Full-text · Article · Mar 2014 · Fluids and Barriers of the CNS
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