Filamin A and Filamin B are co-expressed within neurons during periods of neuronal migration and can physically interact

Sheen, Volney L.; Feng, Yuanyi; Graham, Donna; Takafuta, Toshiro; Shapiro, Sandor S.; Walsh, Christopher A.

doi:10.1093/hmg/11.23.2845

Cited by 134 publications

(121 citation statements)

References 27 publications

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“…We cultured MDCK cells using previously described methods 29,30 . We exposed confluent cultures to 4 µM BFA for the indicated time before fixating them in 4% paraformaldehyde and preparing them for immunofluorescence microscopy.…”

Section: Figurementioning

confidence: 99%

Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex

et al. 2003

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Disruption of human neural precursor proliferation can give rise to a small brain (microcephaly), and failure of neurons to migrate properly can lead to an abnormal arrest of cerebral cortical neurons in proliferative zones near the lateral ventricles (periventricular heterotopia). Here we show that an autosomal recessive condition characterized by microcephaly and periventricular heterotopia 1 maps to chromosome 20 and is caused by mutations in the gene ADP-ribosylation factor guanine nucleotide-exchange factor-2 (ARFGEF2). By northernblot analysis, we found that mouse Arfgef2 mRNA levels are highest during embryonic periods of ongoing neuronal proliferation and migration, and by in situ hybridization, we found that the mRNA is widely distributed throughout the embryonic central nervous system (CNS). ARFGEF2 encodes the large (>200 kDa) brefeldin A (BFA)-inhibited GEF2 protein (BIG2), which is required for vesicle and membrane trafficking from the trans-Golgi network (TGN). Inhibition of BIG2 by BFA, or by a dominant negative ARFGEF2 cDNA, decreases cell proliferation in vitro, suggesting a cell-autonomous regulation of neural expansion. Inhibition of BIG2 also disturbed the intracellular localization of such molecules as E-cadherin and β-catenin by preventing their transport from the Golgi apparatus to the cell surface. Our findings show that vesicle trafficking is an important regulator of proliferation and migration during human cerebral cortical development.Autosomal recessive periventricular heterotopia with microcephaly (ARPHM) is a severe malformation of the cerebral cortex, characterized by severe developmental delay and recurrent infections 1 . No anomalies extrinsic to the CNS, such as dysmorphic features or grossly abnormal endocrine or other conditions, have been observed in individuals with ARPHM. Magnetic resonance imaging of the brains of affected individuals shows notable periventricular heterotopia, resulting from the failure of neurons to migrate normally from the lateral ventricular proliferative zone, where they are formed, to the cerebral cortex ( Fig. 1a-d). Abnormal magnetic resonance image signals in subcortical white matter and elsewhere also suggest a delay in the normal myelination by glial cells.An initial genome-wide screen at 10-cM intervals of two Turkish families with ARPHM identified shared homozygosity at a single locus on chromosome 20q11.21-13.2, which we refined by further marker analysis (Fig. 1e,f). Because the two families had indistinguishable clinical and radiographic features, we assumed that they had an allelic disorder and summed their linkage results. The ARPHM region (66.16-77.75 cM on chromosome 20) that was identical by descent in each of the two families yielded a summed multipoint lod score of 4.41 (Fig. 1g). Two-point analyses gave combined maximal lod scores of 3.28 (pedigree 1 = 1.53 and pedigree 2 = 1.75) at marker D20S109 (Fig. 1h).We sequenced several candidate genes in the minimal linked region and found a different deleterious mutation in ARFGEF2 (encod...

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Section: Figurementioning

confidence: 99%

Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex

et al. 2003

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“…By homology, FLNC is most distant and exclusively expressed in a few tissues, such as heart, skeletal muscles and bladder [11,12]. In contrast, FLNA and FLNB are highly homologous and ubiquitously expressed [13]. FLNA and FLNB are built up of an N-terminal actin-binding domain which is followed by 24 immunoglobulin (Ig)-like repeats, interrupted by two hinge regions.…”

Section: Introductionmentioning

confidence: 99%

Organ-wide profiling in mouse reveals high editing levels of Filamin B mRNA in the musculoskeletal system

et al. 2018

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Adenosine to inosine RNA editing in protein-coding messenger RNAs (mRNAs) potentially leads to changes in the amino acid composition of the encoded proteins. The mRNAs encoding the ubiquitously expressed actin-crosslinking proteins Filamin A and Filamin B undergo RNA editing leading to a highly conserved glutamine to arginine exchange at the identical position in either protein. Here, by targeted amplicon sequencing we analysed the RNA editing of Filamin B across several mouse tissues during post-natal development. We find highest filamin B editing levels in skeletal muscles, cartilage and bones, tissues where Filamin B function seems most important. Through the analysis of Filamin B editing in mice deficient in either ADAR1 or 2, we identified ADAR2 as the enzyme responsible for Filamin B RNA editing. We show that in neuronal tissues Filamin B editing drops in spliced transcripts indicating regulated maturation of edited transcripts. We show further that the variability of Filamin B editing across several organs correlates with its mRNA expression.

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“…2a). Filamin A associates as a homodimer and may heterodimerize with filamin B, the product of a paralogous gene, FLNB 18 .…”

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confidence: 99%

Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans

et al. 2003

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Remodeling of the cytoskeleton is central to the modulation of cell shape and migration. Filamin A, encoded by the gene FLNA, is a widely expressed protein that regulates re-organization of the actin cytoskeleton by interacting with integrins, transmembrane receptor complexes and second messengers 1,2 . We identified localized mutations in FLNA that conserve the reading frame and lead to a broad range of congenital malformations, affecting craniofacial structures, skeleton, brain, viscera and urogenital tract, in four X-linked human disorders: otopalatodigital syndrome types 1 (OPD1; OMIM 311300) and 2 (OPD2; OMIM 304120), frontometaphyseal dysplasia (FMD; OMIM 305620) and Melnick-Needles syndrome (MNS; OMIM 309350). Several mutations are recurrent, and all are clustered into four regions of the gene: the actin-binding domain and rod domain repeats 3, 10 and 14/15. Our findings contrast with previous observations that loss of function of FLNA is embryonic lethal in males but manifests in females as a localized neuronal migration disorder, called periventricular nodular heterotopia (PVNH; refs. 3-6). The patterns of mutation, X-chromosome inactivation and phenotypic manifestations in the newly described mutations indicate that they have gain-of-function effects, implicating filamin A in signaling pathways that mediate organogenesis in multiple systems during embryonic development.

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Filamin A and Filamin B are co-expressed within neurons during periods of neuronal migration and can physically interact

Cited by 134 publications

References 27 publications

Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex

Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex

Organ-wide profiling in mouse reveals high editing levels of Filamin B mRNA in the musculoskeletal system

Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans

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