A Novel CNS Gene Required for Neuronal Migration and Involved in X-Linked Subcortical Laminar Heterotopia and Lissencephaly Syndrome

Portes, Vincent Des; Pinard, Jean Marc; Billuart, Pierre; Vinet, M.; Koulakoff, Annette; Carrié, Alain; Gelot, Antoinette; Dupuis, Elisabeth; Motté, Jacques; Berwald‐Netter, Yoheved; Catala, Martin; Kahn, Axel; Beldjord, Chérif; Chelly, Jamel

doi:10.1016/s0092-8674(00)80898-3

Cited by 701 publications

(499 citation statements)

References 50 publications

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“…41 Mutations in two different genes may result in type I lissencephaly: LIS1, 4 and doublecortin, an X-linked gene. 2,3 The phenotypic presentation of the patients is very similar. However, while the frontal brain is more affected in patients with mutated doublecortin, LIS1 mutations affect mainly the parietal and occipital cortex.…”

Section: Lis1 and Doublecortinmentioning

confidence: 91%

LIS1—no more no less

2002

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Section: Lis1 and Doublecortinmentioning

confidence: 91%

LIS1—no more no less

2002

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“…Because humans with spontaneous mutations in the DCX gene show gross malformation of the cerebral cortex and profound neurological disability (Berg et al, 1998;des Portes et al, 1998;Gleeson et al, 1998), we were surprised that Dcx heterozygotes and hemizygotes showed remarkably normal overall brain morphology. The size of the forebrain, cerebellum, and other major gray matter structures was indistinguishable from normal ( Fig.…”

Section: Mutant Mice Demonstrate Preserved Neocortical Architectumentioning

confidence: 99%

“…Doublecortin was first identified as the causative gene in X-linked lissencephaly/double cortex syndrome (des Portes et al, 1998;Gleeson et al, 1998). It encodes a microtubule-associated protein that is expressed in migrating neuroblasts (Francis et al, 1999;Gleeson et al, 1999a).…”

mentioning

confidence: 99%

Doublecortin Is Required in Mice for Lamination of the Hippocampus But Not the Neocortex

et al. 2002

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Doublecortin (DCX) is a microtubule-associated protein that is required for normal neocortical and hippocampal development in humans. Mutations in the X-linked human DCX gene cause gross neocortical disorganization (lissencephaly or "smooth brain") in hemizygous males, whereas heterozygous females show a mosaic phenotype with a normal cortex as well as a second band of misplaced (heterotopic) neurons beneath the cortex ("double cortex syndrome"). We created a mouse carrying a targeted mutation in the Dcx gene. Hemizygous male Dcx mice show severe postnatal lethality; the few that survive to adulthood are variably fertile. Dcx mutant mice show neocortical lamination that is largely indistinguishable from wild type and show normal patterns of neocortical neurogenesis and neuronal migration. In contrast, the hippocampus of both heterozygous females and hemizygous males shows disrupted lamination that is most severe in the CA3 region. Behavioral tests show defects in context and cued conditioned fear tests, suggesting that deficits in hippocampal learning accompany the abnormal cytoarchitecture.

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“…Doublecortex is also known as doublecortin (DCX), a microtubule binding protein with two actin-binding domains that regulate neuronal migration and located on chromosome Xq22.3-q23 (7)(8)(9)(10)(11). Mutations in the X-linked DCX gene result in lissencephaly, which is a severe brain disorder in newborns and is a result of abnormal neuronal migration (12).…”

Section: Introductionmentioning

confidence: 99%

Ectopic Doublecortin Gene Expression Suppresses the Malignant Phenotype in Glioblastoma Cells

Santra¹,

Zhang²,

Santra³

et al. 2006

Cancer Research

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Doublecortin (DCX) is one of the three genes found from Affymetrix gene chip analysis related to glioma patient survival. Two other genes (e.g., osteonectin and semaphorin 3B) are well characterized as antioncogenic and tumor suppressor genes. However, there is no report about the involvement of DCX in cancer. Here, we show that gene transfer technology into DCX-deficient glioblastoma cell lines, such as A172, U87, U251N, RG2, and 9L, with DCX cDNA significantly suppressed growth of these glioma cells. U87 cells with ectopic expression of DCX exhibit a marked suppression of the transformed phenotype as growth arrested in the G 2 phase of the cell cycle progression, small colony formation in soft agar, and no tumor formation in nude rats. This transformed phenotype can be restored by knocking down DCX expression with DCX small interfering RNA. DCX was highly phosphorylated in glioma cells. Phosphorylation in the glioma cells was greater than in noncancer cells such as mouse NIH 3T3 and human embryonic kidney 293T cells. Coimmunoprecipitation of the phosphorylated DCX and spinophilin/neurabin II from DCX-synthesizing glioma cells indicated their interaction. This interaction would lead to a block of anchorage-independent growth as neurabin II is a synergistic inhibitor of anchorage-independent growth with p14ARF (ARF). Interaction between phosphorylated DCX and neurabin II may induce the association of the protein phosphatase 1 catalytic subunit (PP1) with neurabin II and inactivate PP1 and block mitosis during G 2 and M phases of the cell cycle progression. Thus, DCX seems to be a tumor suppressor of glioma. (Cancer Res 2006; 66(24): 11726-35)

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A Novel CNS Gene Required for Neuronal Migration and Involved in X-Linked Subcortical Laminar Heterotopia and Lissencephaly Syndrome

Cited by 701 publications

References 50 publications

LIS1—no more no less

LIS1—no more no less

Doublecortin Is Required in Mice for Lamination of the Hippocampus But Not the Neocortex

Ectopic Doublecortin Gene Expression Suppresses the Malignant Phenotype in Glioblastoma Cells

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