Mouse orthologue of ARX, a gene mutated in several X‐linked forms of mental retardation and epilepsy, is a marker of adult neural stem cells and forebrain GABAergic neurons

Colombo, Elena; Galli, Rossella; Cossu, Giulio; Gécz, Jozef; Broccoli, Vania

doi:10.1002/dvdy.20164

Cited by 78 publications

(101 citation statements)

References 33 publications

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“…The other primers used have been published. 34,35 All primers were designed to cross an intron/exon boundary. In the case of Arx amplification, 5% DMSO was added to the reaction mix.…”

Section: Methodsmentioning

confidence: 99%

“…RNA probes labeled with digoxigenin-UTP (Roche) were synthesized from linearized cDNA templates according to manufacturer's instructions. A fragment corresponding to the full-length mouse Arx cDNA 34 and a 695-bp fragment corresponding to the 3 0 end of murine Myogenin cDNA were used as riboprobes. For whole-mount X-Gal staining, embryos and isolated muscles were fixed overnight in 4% paraformaldehyde at 41C and stained as described for the sections.…”

Section: Methodsmentioning

confidence: 99%

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The homeobox gene Arx is a novel positive regulator of embryonic myogenesis

Biressi

Messina²,

Collombat

et al. 2007

Cell Death Differ

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Skeletal muscle fibers form in overlapping, but distinct phases that depend on the generation of temporally different lineages of myogenic cells. During primary myogenesis (E10.5-E12.5 in the mouse), embryonic myoblasts fuse homotypically to generate primary fibers, whereas during later development (E14.5-E17.5), fetal myoblasts differentiate into secondary fibers. How these myogenic waves are regulated remains largely unknown. Studies have been hampered by the lack of markers which would distinguish embryonic from fetal myoblast populations. We show here that the homeobox gene Arx is strongly expressed in differentiating embryonic muscle, downstream of myogenic basic helix-loop-helix (bHLH) genes. Its expression progressively decreases during development. When overexpressed in the C2C12 myogenic cell line, Arx enhances differentiation. Accordingly, it stimulates the transcriptional activity from the Myogenin promoter and from multimerized E-boxes when co-expressed with MyoD and Mef2C in CH310T1/2. Furthermore, Arx co-immunoprecipitates with Mef2C, suggesting that it participates in the transcriptional regulatory network acting in embryonic muscle. Finally, embryonic myoblasts isolated from Arx-deficient embryos show a delayed differentiation in vivo together with an enhanced clonogenic capacity in vitro. We propose here that Arx acts as a novel positive regulator of embryonic myogenesis by synergizing with Mef2C and MyoD and by establishing an activating loop with Myogenin.

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“…The other primers used have been published. 34,35 All primers were designed to cross an intron/exon boundary. In the case of Arx amplification, 5% DMSO was added to the reaction mix.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

The homeobox gene Arx is a novel positive regulator of embryonic myogenesis

Biressi

Messina²,

Collombat

et al. 2007

Cell Death Differ

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“…1, available at www.jneurosci.org as supplemental material). In addition, it is localized in proliferating cells in the cortical VZ, but not in radially migrating neurons (Colombo et al, 2004;Poirier et al, 2004;Friocourt et al, 2006). Because some defects in the organization of pyramidal neurons have been reported in Arx mutant mice (Kitamura et al, 2002), we examined the effects of ARX silencing in neuronal progenitors on radial migration.…”

Section: Both Inactivation and Overexpression Of Arx Affect Radial MImentioning

confidence: 99%

“…In the developing cortex, Arx expression is observed in progenitor cells of the VZ as well as in migrating interneurons (Colombo et al, 2004;Poirier et al, 2004;Friocourt et al, 2006). Mutant mice for Arx display a phenotype very similar to the human XLAG (Kitamura et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Cell-Autonomous Roles of ARX in Cell Proliferation and Neuronal Migration during Corticogenesis

Friocourt¹,

Kanatani²,

Tabata³

et al. 2008

J. Neurosci.

118

106

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The aristaless-related homeobox (ARX) gene has been implicated in a wide spectrum of disorders ranging from phenotypes with severe neuronal migration defects, such as lissencephaly, to mild forms of X-linked mental retardation without apparent brain abnormalities. To better understand its role in corticogenesis, we used in utero electroporation to knock down or overexpress ARX. We show here that targeted inhibition of ARX causes cortical progenitor cells to exit the cell cycle prematurely and impairs their migration toward the cortical plate. In contrast, ARX overexpression increases the length of the cell cycle. In addition, we report that RNA interferencemediated inactivation of ARX prevents cells from acquiring multipolar morphology in the subventricular and intermediate zones, resulting in decreased neuronal motility. In contrast, ARX overexpression appears to promote the development of tangentially oriented processes of cells in the subventricular and intermediate zones and affects radial migration of pyramidal neurons. We also demonstrate that the level of ARX expression is important for tangential migration of GABA-containing interneurons, because both inactivation and overexpression of the gene impair their migration from the ganglionic eminence. However, our data suggest that ARX is not directly involved in GABAergic cell fate specification. Overall, these results identify multiple and distinct cell-autonomous roles for ARX in corticogenesis.

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“…High levels of expression are also observed in the subventricular zone, the caudate nucleus, putamen, substantia nigra, corpus callosum, amygdala and hippocampus. [1][2][3]5,6 This expression during early development and predilection for neuronal tissue suggests that ARX has a pivotal function in neurodevelopment.…”

Section: Introductionmentioning

confidence: 99%

Ohtahara syndrome in a family with an ARX protein truncation mutation (c.81C>G/p.Y27X)

et al. 2009

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Aristaless-related homeobox (ARX) gene mutations cause a diverse spectrum of disorders of the human brain, including lissencephaly, various forms of epilepsy and non-syndromic mental retardation. We have identified a novel mutation, c.81C4G (p.Y27X), within the ARX gene in a family with two affected male cousins. One of the boys was diagnosed with an early infantile epileptic encephalopathy also known as Ohtahara syndrome, whereas his cousin had been diagnosed with West syndrome (WS). Both patients have normal genitalia and neither have lissencephaly. The ARX mutation identified is predicted to yield a severely truncated protein of only 26 amino acids and can be considered as a null mutation. Somewhat surprisingly, however, it does not yield the X-linked lissencephaly with ambiguous genitalia (XLAG) syndrome. We proposed that the ARX mRNA translation re-initiated at the next AUG codon at position c.121-123 (aa 41) and, thus, partly rescued these patients from XLAG. Our in vitro studies show that this N-terminally truncated ARX protein (p.M41_C562) is detected by western immunoblot in lysates from cells transiently transfected with an ARX over-expression construct containing the c.81C4G mutation. Although these findings widen the spectrum of clinical phenotypes because of mutations in the ARX gene, they also emphasize the molecular pathogenetic effect of individual mutations as well as the effect of genetic background resulting in intrafamilial clinical heterogeneity for these mutations.

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Mouse orthologue of ARX, a gene mutated in several X‐linked forms of mental retardation and epilepsy, is a marker of adult neural stem cells and forebrain GABAergic neurons

Cited by 78 publications

References 33 publications

The homeobox gene Arx is a novel positive regulator of embryonic myogenesis

The homeobox gene Arx is a novel positive regulator of embryonic myogenesis

Cell-Autonomous Roles of ARX in Cell Proliferation and Neuronal Migration during Corticogenesis

Ohtahara syndrome in a family with an ARX protein truncation mutation (c.81C>G/p.Y27X)

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