X-linked malformations of neuronal migration

Dobyns, William B.; Andermann, Eva; Andermann, F.; Czapansky-Beilman, Desiree; Dubeau, François; Dulac, Olivier; Guerrini, Renzo; Hirsch, Betsy A.; Ledbetter, David H.; Lee, N. S.; Motté, Jacques; Pinard, Jean Marc; Radtke, Rodney A.; Ross, M. Elizabeth; Tampieri, Donatella; Walsh, Christopher A.; Truwit, Chip

doi:10.1212/wnl.47.2.331

Cited by 230 publications

(137 citation statements)

References 29 publications

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“…Many of these cases displayed extensive areas of the lateral ventricles with a disruption of the VZ/ ependyma and displacement of NPCs into the ventricle (Fig. 2I-L Impairment of neuronal migration gives rise to several genetic malformations of the developing cortex: lissencephaly (smooth brain), subcortical band heterotopia (heterotopic neurons arrested under the normal cerebral cortex) and periventricular heterotopia (PH) (Barkovich et al,1991;Ricci et al, 1992;Kamuro and Tenokuchi 1993;Dobyns et al, 1996;Ferland et al, 2009). PHs are clusters of neuroblast/neurons ectopically positioned along the lateral ventricles ( Fig.…”

Section: How and To What Extent Are The Proliferation Mi-gration Andmentioning

confidence: 99%

A cell junction pathology of neural stem cells leads to abnormal neurogenesis and hydrocephalus

et al. 2012

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Most cells of the developing mammalian brain derive from the ventricular (VZ) and the subventricular (SVZ) zones. The VZ is formed by the multipotent radial glia/neural stem cells (NSCs) while the SVZ harbors the rapidly proliferative neural precursor cells (NPCs). Evidence from human and animal models indicates that the common history of hydrocephalus and brain maldevelopment starts early in embryonic life with disruption of the VZ and SVZ. We propose that a "cell junction pathology" involving adherent and gap junctions is a fi nal common outcome of a wide range of gene mutations resulting in proteins abnormally expressed by the VZ cells undergoing disruption. Disruption of the VZ during fetal development implies the loss of NSCs whereas VZ disruption during the perinatal period implies the loss of ependyma. The process of disruption occurs in specifi c regions of the ventricular system and at specifi c stages of brain development. This explains why only certain brain structures have an abnormal development, which in turn results in a specifi c neurological impairment of the newborn. Disruption of the VZ of the Sylvian aqueduct (SA) leads to aqueductal stenosis and hydrocephalus, while disruption of the VZ of telencephalon impairs neurogenesis. We are currently investigating whether grafting of NSCs/neurospheres from normal rats into the CSF of hydrocephalic mutants helps to diminish/repair the outcomes of VZ disruption.

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Section: How and To What Extent Are The Proliferation Mi-gration Andmentioning

confidence: 99%

A cell junction pathology of neural stem cells leads to abnormal neurogenesis and hydrocephalus

et al. 2012

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“…1,4,13,15,16 LIS and SBH are usually more severe anteriorly in patients with DCX mutations, although in the most severe malformations this may not be evident. This has been described as an anterior greater than posterior (A > P) gradient, which differs from the P > A gradient seen in LIS patients with LIS1 deletions or mutations.…”

Section: Introductionmentioning

confidence: 95%

Mutation analysis of the DCX gene and genotype/phenotype correlation in subcortical band heterotopia

et al. 2001

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Subcortical band heterotopia (SBH) comprises part of a spectrum of phenotypes associated with classical lissencephaly (LIS). LIS and SBH are caused by alterations in at least two genes: LIS1 (PAFAH1B1) at 17p13.3 and DCX (doublecortin) at Xq22.3-q23. DCX mutations predominantly cause LIS in hemizygous males and SBH in heterozygous females, and we have evaluated several families with LIS male and SBH female siblings. In this study, we performed detailed DCX mutation analysis and genotype-phenotype correlation in a large cohort with typical SBH. We screened 26 sporadic SBH females and 11 LIS/SBH families for DCX mutations by direct sequencing. We found 29 mutations in 22 sporadic patients and 11 pedigrees, including five deletions, four nonsense mutations, 19 missense mutations and one splice donor site mutation. The DCX mutation prevalence was 84.6% (22 of 26) in sporadic SBH patients and 100% (11 of 11) in SBH pedigrees. Maternal germline mosaicism was found in one family. Significant differences in genotype were found in relation to band thickness and familial vs sporadic status. European Journal of Human Genetics (2001) 9, 5-12.

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“…More severe mutations in ARX, resulting in premature termination of the protein, have been reported in X-linked lissencephaly with abnormal genitalia (XLAG) (Dobyns et al, 1999;Kitamura et al, 2002). Lissencephaly (smooth brain), characterized by massive disorganization of neurons throughout the cortex, is thought to result from a defect in neuronal migration (Dobyns et al, 1996). In addition to ARX, four other genes have so far been shown to be responsible for type I lissencephaly: LIS1, doublecortin (DCX ), reelin (RELN ), and ␣-1 tubulin (TUBA3) (Reiner et al, 1993;des Portes et al, 1998;Gleeson et al, 1998;Hong et al, 2000;Keays et al, 2007).…”

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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X-linked malformations of neuronal migration

Cited by 230 publications

References 29 publications

A cell junction pathology of neural stem cells leads to abnormal neurogenesis and hydrocephalus

A cell junction pathology of neural stem cells leads to abnormal neurogenesis and hydrocephalus

Mutation analysis of the DCX gene and genotype/phenotype correlation in subcortical band heterotopia

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

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