Lis1 and doublecortin function with dynein to mediate coupling of the nucleus to the centrosome in neuronal migration

Tanaka, Teruyuki; Serneo, Finley F.; Higgins, Christine M; Gambello, Michael J.; Wynshaw‐Boris, Anthony; Gleeson, Joseph G.

doi:10.1083/jcb.200309025

Cited by 397 publications

(395 citation statements)

References 66 publications

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“…LIS1, NDEL1 and NDE1 localize to the centrosome [150][151][152][153] and in cells deficient for LIS1, dynein or NDEL1 the distance between the nucleus and centrosome is abnormally large. [158][159][160] This decoupling of the centrosome from the nucleus appears to be due to loss of a specific microtubule bundle known as the microtubule fork/ cage, which connects the two organelles together, 158,159 and is essential for nuclear migration. 161 Disruption of this structure and therefore nucleuscentrosome coupling may be one means by which LIS1/NDEL1 knockdown inhibits nuclear migration.…”

Section: Lis1 Ndel1 Nde1 and Disc1mentioning

confidence: 99%

The DISC locus in psychiatric illness

et al. 2007

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The DISC locus is located at the breakpoint of a balanced t(1;11) chromosomal translocation in a large and unique Scottish family. This translocation segregates in a highly statistically significant manner with a broad diagnosis of psychiatric illness, including schizophrenia, bipolar disorder and major depression, as well as with a narrow diagnosis of schizophrenia alone. Two novel genes were identified at this locus and due to the high prevalence of schizophrenia in this family, they were named Disrupted-in-Schizophrenia-1 (DISC1) and Disrupted-in-Schizophrenia-2 (DISC2). DISC1 encodes a novel multifunctional scaffold protein, whereas DISC2 is a putative noncoding RNA gene antisense to DISC1. A number of independent genetic linkage and association studies in diverse populations support the original linkage findings in the Scottish family and genetic evidence now implicates the DISC locus in susceptibility to schizophrenia, schizoaffective disorder, bipolar disorder and major depression as well as various cognitive traits. Despite this, with the exception of the t(1;11) translocation, robust evidence for a functional variant(s) is still lacking and genetic heterogeneity is likely. Of the two genes identified at this locus, DISC1 has been prioritized as the most probable candidate susceptibility gene for psychiatric illness, as its protein sequence is directly disrupted by the translocation. Much research has been undertaken in recent years to elucidate the biological functions of the DISC1 protein and to further our understanding of how it contributes to the pathogenesis of schizophrenia. These data are the main subject of this review; however, the potential involvement of DISC2 in the pathogenesis of psychiatric illness is also discussed. A detailed picture of DISC1 function is now emerging, which encompasses roles in neurodevelopment, cytoskeletal function and cAMP signalling, and several DISC1 interactors have also been defined as independent genetic susceptibility factors for psychiatric illness. DISC1 is a hub protein in a multidimensional risk pathway for major mental illness, and studies of this pathway are opening up opportunities for a better understanding of causality and possible mechanisms of intervention. Molecular Psychiatry (2008) 13, 36-64; doi:10.1038/sj.mp.4002106; published online 2 October 2007 Keywords: schizophrenia; bipolar disorder; depression; DISC1; DISC2; mouse models Genetics of DISC1 discoverySt Clair et al. 1 first reported a Scottish family with a high loading of major mental illness, which cosegregates with a t(1;11) translocation. Long-term follow-up of this family over a period of 30 years has reported 87 family members, of whom 37 carry the translocation. 2 Of 29 individuals carrying the translocation, for whom psychiatric assessment was possible, 7 have a diagnosis of schizophrenia, 1 has a diagnosis of bipolar disorder and 10 cases of recurrent major depression were also reported. 2 Thus, 18 of 29 translocation carriers are diagnosed with major mental illness whereas none of...

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Section: Lis1 Ndel1 Nde1 and Disc1mentioning

confidence: 99%

The DISC locus in psychiatric illness

et al. 2007

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“…Translocation of the nucleus towards the position of the centrosome 42 . As DCX localizes to the microtubules of the perinuclear cage, the leading process and the growth cones [43][44][45] , we examined for defects in each of these. We first tested for a defect in the latter two events.…”

Section: Decreased Migration Of Neurons Exiting Svza But No Apparentmentioning

confidence: 99%

“…We first tested for a defect in the latter two events. The N-C distance (distance between the centrosome and the leading edge of the nucleus) is thought to reflect a dynamic interplay between movement of these two organelles, and altered N-C distance has been proposed to underlie the migration defect in some cell models [45][46][47][48] .…”

Section: Decreased Migration Of Neurons Exiting Svza But No Apparentmentioning

confidence: 99%

“…Indeed, disruption of dynein function, or alterations in LIS1 or Ndel1, which are dynein components, similarly lead to alterations in this coupling, as measured by an increased distance between the nucleus and centrosome (i.e. coupling) 45,46 . It was previously demonstrated that overexpression of DCX led to an amelioration of the migration defects in Lis1 +/-neurons and corrected the nuclear-centrosome coupling defect 45 .…”

Section: Plays An Essential Role In Translocation Of the Nucleusmentioning

confidence: 99%

“…coupling) 45,46 . It was previously demonstrated that overexpression of DCX led to an amelioration of the migration defects in Lis1 +/-neurons and corrected the nuclear-centrosome coupling defect 45 . We now show that deletion of Dcx leads to a defect in nuclear translocation that was not evident by measurement of N-C coupling alone.…”

Section: Plays An Essential Role In Translocation Of the Nucleusmentioning

confidence: 99%

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Doublecortin maintains bipolar shape and nuclear translocation during migration in the adult forebrain

et al. 2006

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The ability of the mature mammalian nervous system to continually produce neuronal precursors is of considerable importance, as manipulation of this process might one day permit the replacement of cells lost as a result of injury or disease. In mammals, the anterior subventricular zone (SVZa) region is one of the primary sites of adult neurogenesis. Here we show that Doublecortin (DCX), a widely used marker for newly generated neurons, when deleted in mouse results in a severe morphological defect in the rostral migratory stream and delayed neuronal migration that is independent of direction or responsiveness to Slit chemorepulsion. DCX is required for nuclear translocation and maintenance of bipolar morphology during migration of these cells. Our data identifies a critical function for DCX in the movement of newly generated neurons in the adult brain.In the rodent and primate brain, the anterior region of the lateral ventricle and the hippocampus are the primary sites of adult neurogenesis [1][2][3][4][5][6][7] . These neuroblasts, upon completing migration, are capable of maturing into fully differentiated neurons, integrating into local synaptic circuits and may be important in adult cognitive processing [8][9][10][11] .The mechanisms controlling the targeted translocation of large numbers of cells to the olfactory bulb (OB) over a considerable distance (>5 mm in the adult mouse) are an issue of intense investigation. These neurons translocate using a process known as chain migration, whereby the cells use each other as the migratory substrate 12 . These newly generated neurons are derived from SVZa glial fibrillary acidic protein (GFAP)-positive astrocytes 13,14 , which also ensheath them as they move through extensive interconnected networks along the lining of the lateral ventricle in the rostral forebrain and the rostral migratory stream (RMS) 15 . There, they are under the control of extracellular migration guidance cues, including the secreted ligands Slit and Reelin [16][17][18][19] , the receptors ErbB4 and Deleted in Colorectal Carcinoma (DCC) 20,21 , as well as integrins and neural cell adhesion molecule [21][22][23] . Upon reaching the bulb, the neurons turn and migrate in a radial direction 24 , integrating into either the granule cell layer or the periglomerular network 25 . 3The X-linked gene doublecortin (DCX) is mutated in some patients with the severe neuronal migration defect called classical lissencephaly or double cortex syndrome 26,27 . This migration defect is likely to be cell autonomous, because in females with a heterozygous mutation, approximately half of the neurons are misplaced within the cerebral cortex as would be expected from random X-chromosome inactivation. As a result, males display a four-layered agyric cortex and females display a subcortical band of heterotopic neurons. It was surprising, therefore, that the Dcx knockout mice displayed no appreciable defect in cortical neuronal lamination or positioning 28 . One possible explanation for these species differences ...

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Tubulin mutations in neurodevelopmental disorders as a tool to decipher microtubule function

Fourel

Boscheron

2020

FEBS Letters

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Malformations of cortical development (MCDs) are a group of severe brain malformations associated with intellectual disability and refractory childhood epilepsy. Human missense heterozygous mutations in the 9 α‐tubulin and 10 β‐tubulin isoforms forming the heterodimers that assemble into microtubules (MTs) were found to cause MCDs. However, how a single mutated residue in a given tubulin isoform can perturb the entire microtubule population in a neuronal cell remains a crucial question. Here, we examined 85 MCD‐associated tubulin mutations occurring in TUBA1A, TUBB2, and TUBB3 and their location in a three‐dimensional (3D) microtubule cylinder. Mutations hitting residues exposed on the outer microtubule surface are likely to alter microtubule association with partners, while alteration of intradimer contacts may impair dimer stability and straightness. Other types of mutations are predicted to alter interdimer and lateral contacts, which are responsible for microtubule cohesion, rigidity, and dynamics. MCD‐associated tubulin mutations surprisingly fall into all categories, thus providing unexpected insights into how a single mutation may impair microtubule function and elicit dominant effects in neurons.

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Lis1 and doublecortin function with dynein to mediate coupling of the nucleus to the centrosome in neuronal migration

Cited by 397 publications

References 66 publications

The DISC locus in psychiatric illness

The DISC locus in psychiatric illness

Doublecortin maintains bipolar shape and nuclear translocation during migration in the adult forebrain

Tubulin mutations in neurodevelopmental disorders as a tool to decipher microtubule function

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