Intra- and Extracellular Control of Neuronal Migration: Relevance to Cortical Malformations

Mutation of the α-tubulin Tuba1a leads to straighter microtubules and perturbs neuronal migration

The Journal of Cell Biology ◽

10.1083/jcb.201607074 ◽

2017 ◽

Vol 216 (8) ◽

pp. 2443-2461 ◽

Cited By ~ 29

Author(s):

Richard Belvindrah ◽

Kathiresan Natarajan ◽

Preety Shabajee ◽

Elodie Bruel-Jungerman ◽

Jennifer Bernard ◽

...

Keyword(s):

Missense Mutation ◽

Glial Cells ◽

Neuronal Migration ◽

Cortical Malformations ◽

Tubulin Isotype ◽

Modeling Data ◽

Migratory Stream ◽

Β Tubulin

Brain development involves extensive migration of neurons. Microtubules (MTs) are key cellular effectors of neuronal displacement that are assembled from α/β-tubulin heterodimers. Mutation of the α-tubulin isotype TUBA1A is associated with cortical malformations in humans. In this study, we provide detailed in vivo and in vitro analyses of Tuba1a mutants. In mice carrying a Tuba1a missense mutation (S140G), neurons accumulate, and glial cells are dispersed along the rostral migratory stream in postnatal and adult brains. Live imaging of Tuba1a-mutant neurons revealed slowed migration and increased neuronal branching, which correlated with directionality alterations and perturbed nucleus–centrosome (N–C) coupling. Tuba1a mutation led to increased straightness of newly polymerized MTs, and structural modeling data suggest a conformational change in the α/β-tubulin heterodimer. We show that Tuba8, another α-tubulin isotype previously associated with cortical malformations, has altered function compared with Tuba1a. Our work shows that Tuba1a plays an essential, noncompensated role in neuronal saltatory migration in vivo and highlights the importance of MT flexibility in N–C coupling and neuronal-branching regulation during neuronal migration.

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Defects of neuronal migration and the pathogenesis of cortical malformations are associated with Small eye (Sey) in the mouse, a point mutation at the Pax-6-locus

Acta Neuropathologica ◽

10.1007/bf00334879 ◽

1993 ◽

Vol 86 (2) ◽

pp. 126-135 ◽

Cited By ~ 113

Author(s):

Wolfgang Schmahl ◽

Monika Knoedlseder ◽

Jack Favor ◽

Duncan Davidson

Keyword(s):

Point Mutation ◽

Neuronal Migration ◽

Cortical Malformations

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Defects of neuronal migration and the pathogenesis of cortical malformations

Progress in Brain Research - Biochemical Basis of Functional Neuroteratology - Permanent Effects of Chemicals on the Developing Brain ◽

10.1016/s0079-6123(08)60494-x ◽

1988 ◽

pp. 15-37 ◽

Cited By ~ 204

Author(s):

Pasko Rakic ◽

D.F. Swaab

Keyword(s):

Neuronal Migration ◽

Cortical Malformations

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Germline and somatic mutations in cortical malformations: Molecular defects in Argentinean patients with neuronal migration disorders

PLoS ONE ◽

10.1371/journal.pone.0185103 ◽

2017 ◽

Vol 12 (9) ◽

pp. e0185103 ◽

Cited By ~ 11

Author(s):

Dolores González-Morón ◽

Sebastián Vishnopolska ◽

Damián Consalvo ◽

Nancy Medina ◽

Marcelo Marti ◽

...

Keyword(s):

Neuronal Migration ◽

Somatic Mutations ◽

Molecular Defects ◽

Cortical Malformations ◽

Neuronal Migration Disorders ◽

Migration Disorders

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Functional characterization of RELN missense mutations involved in recessive and dominant forms of Neuronal Migration Disorders

10.1101/2021.05.25.445586 ◽

2021 ◽

Author(s):

Martina Riva ◽

Sofia Ferreira ◽

Vera P. Medvedeva ◽

Frédéric Causeret ◽

Olivia J. Henry ◽

...

Keyword(s):

Neuronal Migration ◽

De Novo ◽

Functional Characterization ◽

Valuable Insight ◽

Embryonic Mouse ◽

Cortical Malformations ◽

Neuronal Migration Disorders ◽

Migration Disorders

RELN is a large secreted glycoprotein that acts at multiple steps of cerebral cortex development, including neuronal migration. Only recessive mutations of the Reelin gene (RELN) have been associated with human cortical malformations and none has been functionally characterized. We identified novel missense RELN mutations in both compound and de novo heterozygous patients exhibiting an array of neuronal migration disorders (NMDs) as diverse as pachygyria, polymicrogyria and heterotopia. Most mutations caused defective RELN secretion in vitro and, when ectopically expressed in the embryonic mouse cortex, affected neuronal aggregation and/or migration in vivo. We determined the de novo heterozygous mutations acted as dominant negative and demonstrated that RELN mutations mediate not only recessive, but also dominant NMDs. This work assesses for the first time the pathogenicity of RELN mutations showing a strong genotype-phenotype correlation. In particular, the behavior of the mutant proteins in vitro and in vivo predicts the severity of cortical malformations and provides valuable insight into the pathogenesis of these disorders.

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