Causal heterogeneity in isolated lissencephaly

Dobyns, William B.; Elias, Ellen Roy; Newlin, Anna; Pagon, R. A.; Ledbetter, David H.

doi:10.1212/wnl.42.7.1375

Cited by 125 publications

(59 citation statements)

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“…17, 18, 23, and 26). The subcortical band heterotopias and the three-to four-layered cortex mimick the spectrum of neocortical patterns encountered in the subcortical, corticosubcortical, and intracortical migration blockades of the human double cortex and pachygyrias͞lissencephalies (27,28) and of the rat after prenatal irradiation (29). Ectopias and protrusions of neurons noted in layer I (obtained with ibotenate at low doses) display some similarities with the disorders of neuronal migration produced by cryolesions in newborn rat by Dvorak et al (30,31) and with status verrucosus deforman observed in the human (17).…”

Section: Discussionmentioning

confidence: 84%

Arrest of neuronal migration by excitatory amino acids in hamster developing brain

Marret

Gressèns

Evrard

1996

Proc. Natl. Acad. Sci. U.S.A.

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The inf luence of the excitotoxic cascade on the developing brain was investigated using ibotenate, a glutamatergic agonist of both N-methyl-D-aspartate (NMDA) ionotropic receptors and metabotropic receptors. Injected in the neopallium of the golden hamster at the time of production of neurons normally destined for layers IV, III, and II, ibotenate induces arrests of migrating neurons at different distances from the germinative zone within the radial migratory corridors. The resulting cytoarchitectonic patterns include periventricular nodular heterotopias, subcortical band heterotopias, and intracortical arrests of migrating neurons. The radial glial cells and the extracellular matrix are free of detectable damage that could suggest a defect in their guiding role. The migration disorders are prevented by coinjection of DL-2-amino-7-phosphoheptanoic acid, an NMDA ionotropic antagonist, but are not prevented by coinjection of L(؉)-2-amino-3-phosphonopropionic acid, a metabotropic antagonist. This implies that an excess of ionic inf lux through the NMDA channels of neurons alters the metabolic pathways supporting neuronal migration. Ibotenate, a unique molecular trigger of the excitotoxic cascade, produces a wide spectrum of abnormal neuronal migration patterns recognized in mammals, including the neocortical deviations encountered in the human brain.In targeted postmigratory neurons, excitatory amino acids trigger a calcium-dependent death (1-4). At each developmental step after completion of neocortical neuronal migration, the excitotoxic cascade produces a timed set of laminar and multilaminar neuronal depopulations. It mimics all lesional brain patterns described after hypoxia occurring in human fetuses and neonates between 20 and 40 weeks of gestation (3-6). In contrast, no excitotoxic destructive effect has been reported before maturation of N-methyl-D-aspartate (NMDA) receptors and before acquisition of postmigratory neuronal aerobiosis. In seminal observations performed in organotypic tissue cultures, Komuro and Rakic (7) reported accelerations and decelerations of cerebellar neuronal migration under the influence of excitatory amino acids. The present paper reports neuronal migration disorders induced in vivo in hamster by ibotenate, a glutamatergic agonist, and uses this model to approach the pathophysiology of these frequent neurodevelopmental disturbances. MATERIALS AND METHODSAnimal Handling and Injections of Ibotenate and of Other Glutamatergic Agents. Golden hamsters were chosen for this study because of the timing of brain development in this species. As regards neuronal migration in the neopallium, the newborn hamster is at a stage similar to that of the human fetus at 15 weeks of gestation and at a stage comparable to that of the mouse at the 17th embryonic day. Pregnant female golden hamsters were allowed to deliver on day 16 of gestation. Several successive litters of newborn hamsters of both sexes were used for the experiments. Ibotenate, a glutamatergic agonist, activates both NMDA ion...

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Section: Discussionmentioning

confidence: 84%

Arrest of neuronal migration by excitatory amino acids in hamster developing brain

Marret

Gressèns

Evrard

1996

Proc. Natl. Acad. Sci. U.S.A.

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“…Isolated lissencephaly sequence (ILS) is a heterogeneous disorder consisting of variably severe lissencephaly with no other major malformations, whereas Miller-Dieker syndrome (MDS) consists of a generally more severe classical lissencephaly than ILS, characteristic craniofacial anomalies (microcephaly with bitemporal narrowing, a high forehead, a small nose with anteverted nares, thin vermilion border, and micrognathia), and occasionally other malformations (Dobyns et al 1984). Children with ILS and MDS are severely retarded, have epilepsy, and usu-ally die early in childhood (Dobyns et al 1992). MDS and some cases of ILS are the result of haploinsufficiency at human chromosome 17p13.3.…”

Section: Human Lissencephaly and Lis1mentioning

confidence: 99%

LIS1 and dynein motor function in neuronal migration and development

2001

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Neuronal migration has been studied extensively for over 30 years in diverse mammalian species from the mouse to human. The sequence of events that occurs during cortical development is shared by all of these species (for reviews, see Gleeson and Walsh 2000;Walsh and Goffinet 2000). At the time of neurogenesis, neural precursors proliferate and differentiate into young postmitotic neurons. These postmitotic immature neurons migrate from the ventricular zone (VZ) to a layer called the preplate at the surface of the developing cerebral cortex. The first migrating neurons split the preplate and form the cortical plate, which develops into the cortex. As migration from the VZ continues, cortical lamination is established in an inside-out fashion. The earliest-born neurons end up deep in the cortex, as later-born neurons migrate past them toward the pial surface to establish more superficial layers of the cortex. The latest-born neurons reside near the pial surface. In the final stages of cortical development, synaptogenesis and apoptotic elimination of populations of neurons occur. Physically, the migration of neurons require the same three steps necessary for migration of any cell: The extension of the leading edge that explores its environment for attractive and repulsive signals; the movement of the nucleus into the leading process, called nucleokinesis; and the retraction of the trailing process.The understanding of the process of mammalian neuronal migration resulted primarily from neurobiological studies of brain development in normal mammals and mutant mice such as reeler. These studies provided important insight into the laminar development of the CNS. However, they did not identify the genetic and developmental pathways that regulate neuronal migration. Cloning of disease genes for human neuronal migration defects and mouse mutants have provided critical entry points into these pathways, whereas genetic and cell biological studies have guided our understanding of the function of these gene products in neuronal migration. For example, cloning of the gene mutated in reeler and the identification of its protein product RELN led to the elucidation of a RELN-dependent signal transduction pathway (for recent review, see Rice and Curran 1999). Other genes have been identified that are responsible for neuronal migration defects in the human (LIS1 and DCX) and mouse (Cdk5 and its required activators p35 and p39), but until recently, the relationship between these genes involved in migration were unknown.Several recent studies have demonstrated that LIS1, the protein product of a gene mutated in the human neuronal migration defect lissencephaly, binds to and regulates dynein motor function in the cell. These studies place LIS1 in the midst of a well-studied motor complex important for several critical cell functions and perhaps provide a context for integrating several neuronal migration pathways. In this review, we will provide some background on the human and mouse studies that provided the entry points to neuronal...

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“…[6][7][8][9][10] Mutations of DCX have been detected in males with isolated lissencephaly sequence (ILS), 11 and in females with SBH. 4,[12][13][14][15] although rare examples of males with SBH 16 and females with lissencephaly 17 have been reported.…”

Section: Introductionmentioning

confidence: 99%

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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Causal heterogeneity in isolated lissencephaly

Cited by 125 publications

References 0 publications

Arrest of neuronal migration by excitatory amino acids in hamster developing brain

Arrest of neuronal migration by excitatory amino acids in hamster developing brain

LIS1 and dynein motor function in neuronal migration and development

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

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