Role of cytoskeletal abnormalities in the neuropathology and pathophysiology of type I lissencephaly

Friocourt, Gaëlle; Marcorelles, Pascale; Saugier-Veber, Pascale; Quillé, Marie-Lise; Marret, Stéphane; Laquerrière, Annie

doi:10.1007/s00401-010-0768-9

Cited by 46 publications

(46 citation statements)

References 171 publications

(311 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cortical malformations are recovered in the human populations at a surprisingly high rate and can be familial or arise spontaneously de novo (1)(2)(3)28). One manifestation of cortical malformation is subcortical band heterotopia (SBH) and lissencephaly (LIS; smooth brain).…”

Section: Discussionmentioning

confidence: 99%

“…We thus used dendrite enhancement by Dcx expression as an assay for wild type Dcx function, using previously described MT binding-competent and MT bindingdeficient mutants (25)(26)(27). All of these alleles were originally identified in patients with lissencephaly (2,28,29). We found that Dcx alleles that retain MT binding but lack the C-terminal regions (required for spn and AP adaptor binding) are defective for dendrite growth promotion (i.e.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Different Doublecortin (DCX) Patient Alleles Show Distinct Phenotypes in Cultured Neurons

Yap

Digilio

McMahon

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by Velia FowlerDoublecortin on the X-chromosome (DCX) is a neuronal microtubule-binding protein with a multitude of roles in neurodevelopment. In humans, DCX is a major genetic locus for X-linked lissencephaly. The best studied defects are in neuronal migration during corticogenesis and in the hippocampus, as well as axon and dendrite growth defects. Much effort has been directed at understanding the molecular and cellular bases of DCX-linked lissencephaly. The focus has been in particular on defects in microtubule assembly and bundling, using knock-out mice and expression of WT and mutant Dcx in non-neuronal cells. Dcx also binds other proteins besides microtubules, such as spinophilin (abbreviated spn; gene name Ppp1r9b protein phosphatase 1 regulatory subunit 9b) and the clathrin adaptors AP-1 and AP-2. Even though many non-sense and missense mutations of Dcx are known, their molecular and cellular defects are still only incompletely understood. It is also largely unknown how neurons are affected by expression of DCX patient alleles. We have now characterized several patient DCX alleles (DCX-R89G, DCX-R59H, DCX-246X, DCX-272X, and DCX-303X) using a gain-of-function dendrite growth assay in cultured rat neurons in combination with the determination of molecular binding activities and subcellular localization in non-neuronal and neuronal cells. First, we find that several mutants (Dcx-R89G and Dcx-272X) were loss-of-function alleles (as had been postulated) but surprisingly acted via different cellular mechanisms. Second, one allele (Dcx-R59H) formed cytoplasmic aggregates, which contained Hspa1B (heat shock protein 1B hsp70) and ubiquitinated proteins, trapped other cytoskeletal proteins, including spinophilin, and led to increased autophagy. This allele could thus be categorized as "off-pathway"/possibly neomorph. Our findings thus suggested that distinct DCX alleles caused dysfunction by different mechanisms. Dcx4 is a neuronal microtubule (MT)-binding protein with many roles in neurodevelopment. In humans, DCX is a major locus for X-linked lissencephaly (1-3) presenting with cortical, hippocampal, and cerebellar defects and defects in major axon tracts (4 -7). Much effort has thus been directed at understanding the molecular and cellular bases for this disease, with a particular focus on DCX-dependent defects in MT assembly and bundling. Experiments using a Dcx knock-out mouse, or double knockouts with the related genes Dclk1 and Dclk2 (8 -14), or overexpression approaches (15) all argue strongly that Dcx does in fact play important roles in neurodevelopmental processes. The best studied defects are in neuronal migration in cortex (14, 16) and in hippocampus (17, 18). Axon and dendrite defects have also been described (6, 10, 17). For instance, dendrites in hippocampal pyramidal neurons are simplified in adult Dcx KO mice (17). Dendrite growth is also impaired in cortical neurons cultured from Dclk1/Dcx double knock-out embryos (8). Furthermore, short hairpin-mediated knockdown of Dcx in cultured rat...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Different Doublecortin (DCX) Patient Alleles Show Distinct Phenotypes in Cultured Neurons

Yap

Digilio

McMahon

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…7 Functional studies suggest that abnormal neuronal migration would result from defective interactions in the tubulin heterodimer assembly and altered three-dimensional conformation of the tubulins, with compromised interaction with microtubule-associated proteins or microtubule motors. 11 This study brings to eight the number of individuals with TUBB2B mutations reported so far. We identified three new TUBB2B mutations in as many unrelated patients with rather symmetrical malformations of cortical development, including polymicrogyria in two patients, one having a cobblestone-like cortex, and bilateral regional pachygyria in one.…”

Section: Discussionmentioning

confidence: 99%

Symmetric polymicrogyria and pachygyria associated with TUBB2B gene mutations

et al. 2012

View full text Add to dashboard Cite

The purpose of the study is to explore the causative role of TUBB2B gene mutations in patients with different malformations of cortical development. We collected and evaluated clinical and MRI data of a cohort of 128 consecutive patients (61 females and 67 males) in whom brain MRI had detected a spectrum of malformations of cortical development including polymicrogyria or pachygyria, who were mutation-negative to other possible causative genes. Mutation analysis of the TUBB2B gene was performed. We identified three new TUBB2B mutations in three unrelated patients (3 out of 128; 2.3%) with a diffuse and rather symmetrical cortical abnormality, including diffuse polymicrogyria in two and bilateral regional pachygyria in one. One patient harbored a p.Asp417Asn amino-acid substitution in the C-terminal domain of the protein; one patient a p.Asn256Ser amino-acid substitution in the intermediate domain and one patient a p.Leu117Pro amino-acid substitution in the N-terminal domain. The localization of each mutation within the secondary structure of the b2-tubulin polypeptide suggests that these mutations might alter the proper functions of microtubules. The phenotypic spectrum associated with TUBB2B mutations is wider than previously reported and includes diffuse, symmetric malformations of cortical development. Keywords: malformations of cortical development; TUBB2B; tubulins; mutation analysis INTRODUCTION Polymicrogyria is a common cortical malformation characterized by an excessive number of abnormally small gyri that result in an irregular cortical surface with lumpy aspect. Brain pathology demonstrates abnormal development or loss of neurons in middle and deep cortical layers, variably associated with an unlayered cortical structure. 1,2 Several genes have been associated with polymicrogyria, including GPR56, SRPX2, TUBB2B, TUBB3, PAX6, TBR2, KIAA1279, NHEJ1, RAB3GAP1 and TUBA8 2-4 with all but GPR56, TUBB3 and TUBB2B found in rare syndromes. Mutations in TUBB2B have been reported in four patients and in one fetus with complex brain dysgenesis with asymmetrical, anteriorly predominant polymicrogyria. 5 We performed TUBB2B mutation analysis in 128 patients in whom brain MRI had detected a spectrum of malformations of cortical development including polymicrogyria or pachygyria, to investigate how common TUBB2B mutations are in this spectrum of malformations and whether previously suggested imaging criteria need to be expanded.

show abstract

“…It has been shown that Reelin interacts, via membrane receptors, with motor and cytoskeletal proteins [94,95], likely targets of calcium dependent pathways. Actually, it has been shown that the product of the LIS1 gene, whose mutation leads to Type I lissencephaly, regulates in a calcium influx-dependent way some RhoGTPases involved in cytoskeletal dynamics [96].…”

Section: Calcium Signalling and Neuronal Migration Disordersmentioning

confidence: 99%

“…It can be envisioned that future focus will be, more than on calcium signalling per se, on the field of calcium-dependent proteins involved in cytoskeletal organization and in organelle trafficking, as pointed by the Reelinlissencephaly case [94][95][96]. However, it cannot be excluded that the TRP channel superfamily, just a newcomer in this context, may provide some surprise -and some unexpected answers.…”

Section: Conclusion and Future Developmentsmentioning

confidence: 99%

Calcium Signaling in Neuronal Motility: Pharmacological Tools for Investigating Specific Pathways

Lovisolo

Ariano²,

Distasi³

2012

CMC

View full text Add to dashboard Cite

Migration of neurons and neuronal precursors from the site of origin to their final location is a key process in the development of the nervous system and in the correct organization of neuronal structures and circuits. Different modes of migration (mainly radial and tangential) have been described in the last 40 years; for these, as for motility processes involving other cellular types, calcium signalling plays a key role, with influx from the extracellular medium representing the main mechanism, and a more delimited but specific role played by release from intracellular stores.Deciphering the involvement of the different calcium influx pathways has been a major task for cellular neurobiologists, and the availability -or lack -of reliable and selective pharmacological tools has represented the main limiting factor. This review addresses the strategies employed to investigate the role of voltage-dependent calcium channels and of neurotransmitter activated channels, either calcium permeable or not, that directly or indirectly can elicit cytosolic calcium increases; in addition, reference to recent findings on the involvement of other families of calcium permeable channels (such as the transient receptor potential superfamily) is presented. Finally, a brief description of the present -and limited -knowledge of the perturbations of calcium signalling involved in neuronal migration pathologies is provided.

show abstract

Role of cytoskeletal abnormalities in the neuropathology and pathophysiology of type I lissencephaly

Cited by 46 publications

References 171 publications

Different Doublecortin (DCX) Patient Alleles Show Distinct Phenotypes in Cultured Neurons

Different Doublecortin (DCX) Patient Alleles Show Distinct Phenotypes in Cultured Neurons

Symmetric polymicrogyria and pachygyria associated with TUBB2B gene mutations

Calcium Signaling in Neuronal Motility: Pharmacological Tools for Investigating Specific Pathways

Contact Info

Product

Resources

About