Disruption of neural progenitors along the ventricular and subventricular zones in periventricular heterotopia.

Department of Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
Human Molecular Genetics (Impact Factor: 6.68). 12/2008; 18(3):497-516. DOI: 10.1093/hmg/ddn377
Source: PubMed

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.

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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.
    Journal of Cell Science 08/2014; 127(19). DOI:10.1242/jcs.144899 · 5.33 Impact Factor
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    • "EMERGING ROLES OF CORTICAL STEM CELLS: IT TAKES MORE THAN NEUROGENESIS TO GYRATE Cortical expansion and folding are commonly simplified as a problem of generating sufficient numbers of neurons (Kornack and Rakic, 1998; Kriegstein et al., 2006; Martinez-Cerdeno et al., 2006; Hansen et al., 2010; Fietz and Huttner, 2011). This notion is actually in agreement with human genetic studies, showing that cortical malformations occur upon mutation of genes expressed by cortical progenitors, such as WDR62, ASPM, FGFR3, FLN1A, and GPR56 (Fox et al., 1998; Bond et al., 2002; Piao et al., 2004; Hevner, 2005; Ferland et al., 2009; Bilguvar et al., 2010; Nicholas et al., 2010; Yu et al., 2010). Accordingly , mouse mutations forcing an increased proliferation , or decreased cell death, of cortical stem cells result in a massively overgrown cerebral cortex, frequently accompanied by the formation of folds or bulges of cortical tissue (Haydar et al., 1999; Chenn and Walsh, 2002; Kingsbury et al., 2003; Depaepe et al., 2005; Lien et al., 2006; Siegenthaler et al., 2009; Wilson et al., in press). "
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    ABSTRACT: Expansion and folding of the cerebral cortex are landmark features of mammalian brain evolution, which are recapitulated during embryonic development. Neural stem cells and their derived germinal cells are coordinated during cerebral cortex development to produce the appropriate amounts and types of neurons. This process is further complicated in gyrencephalic species, where newborn neurons must disperse in the tangential axis to expand the cerebral cortex in surface area. Here, we review advances that have been made over the last decade in understanding the nature and diversity of telencephalic neural stem cells and their roles in cortical development, and we discuss recent progress on how newly identified types of cortical progenitor cell populations may have evolved to drive the expansion and folding of the mammalian cerebral cortex.
    Developmental Neurobiology 07/2012; 72(7):955-71. DOI:10.1002/dneu.22013 · 4.19 Impact Factor
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    • "The absence of PH may reflect the fact that the mice are late embryonic lethal and heterotopia formation may not yet have occurred at this stage of development. Alternatively, we have previously shown that disruption of the neuroependymal lining can lead to nodular heterotopia with loss of BIG2, the second gene mutation in humans that causes PH (unpublished observations and Ferland et al., 2009). In this context, it is possible that the mechanical stressors in the human neuroepithlium may be greater than that in the mouse and that loss of FlnA function alone is not sufficient to cause PH formation in mice. "
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    ABSTRACT: Cytoskeleton-associated proteins play key roles not only in regulating cell morphology and migration but also in proliferation. Mutations in the cytoskeleton-associated gene filamin A (FlnA) cause the human disorder periventricular heterotopia (PH). PH is a disorder of neural stem cell development that is characterized by disruption of progenitors along the ventricular epithelium and subsequent formation of ectopic neuronal nodules. FlnA-dependent regulation of cytoskeletal dynamics is thought to direct neural progenitor migration and proliferation. Here we show that embryonic FlnA-null mice exhibited a reduction in brain size and decline in neural progenitor numbers over time. The drop in the progenitor population was not attributable to cell death or changes in premature differentiation, but to prolonged cell cycle duration. Suppression of FlnA led to prolongation of the entire cell cycle length, principally in M phase. FlnA loss impaired degradation of cyclin B1-related proteins, thereby delaying the onset and progression through mitosis. We found that the cdk1 kinase Wee1 bound FlnA, demonstrated increased expression levels after loss of FlnA function, and was associated with increased phosphorylation of cdk1. Phosphorylation of cdk1 inhibited activation of the anaphase promoting complex degradation system, which was responsible for cyclin B1 degradation and progression through mitosis. Collectively, our results demonstrate a molecular mechanism whereby FlnA loss impaired G2 to M phase entry, leading to cell cycle prolongation, compromised neural progenitor proliferation, and reduced brain size.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 05/2012; 32(22):7672-84. DOI:10.1523/JNEUROSCI.0894-12.2012 · 6.75 Impact Factor
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