Dysfunction of the Orleans reeler gene arising from exon skipping due to transposition of a full-length copy of an active L1 sequence into the skipped exon

Takahara, Tokuei; Ohsumi, Tatsuya; Kuromitsu, Junro; Shibata, Kazuhiro; Sasaki, Nobuya; Okazaki, Yasushi; Shibata, Hideo; Sato, Shigeo; Yoshiki, Atsushi; Kusakabe, Moriaki; Muramatsu, Masami; Ueki, Minoru; Okuda, Kiyoji; Hayashizaki, Yoshihide

doi:10.1093/hmg/5.7.989

Cited by 96 publications

(57 citation statements)

References 24 publications

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“…L1 insertion at this site leads to exon skipping and the 220 bp deletion in the Reelin gene that results in the reeler phenotype (Takahara et al, 1996). An additional reverse primer was designed to the 5Ј end of the L1 element.…”

Section: Methodsmentioning

confidence: 99%

Layer Positioning of Late-Born Cortical Interneurons Is Dependent on Reelin But Not p35 Signaling

Hammond

Gunnersen

et al. 2006

J. Neurosci.

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We tested the response of interneurons to the absence of Reelin signaling or p35 in the mouse neocortex. We provide three independent strands of evidence to demonstrate that layering of late-born (but not early-born) interneurons is regulated by Reelin signaling. First, early-born and late-born interneurons behaved differently in mice lacking Reelin or disabled 1 (Dab1). Early-born interneurons showed layer inversion, whereas late-born interneurons did not demonstrate layer inversion but were randomly distributed across the cortex. Second, in p35 mutant brains (in which Reelin signaling is intact), late-born interneurons are appropriately positioned in the upper layers despite the malpositioning of all other cortical neurons in these mice. Third, transplanted late-born interneuron precursors (wild type) into Dab1 Ϫ/Ϫ cortices showed appropriate upper layer segregation. Together, these results indicate that, in the absence of Reelin signaling, late-born interneurons fail to laminate properly, and this is restored in an environment in which Reelin signaling is intact. These studies suggest different mechanisms for the stratification of cortical interneurons. Whereas the early-born interneurons appear to be associated with projection neuron layering, late-born interneurons rely on Reelin signaling for their correct lamination.

show abstract

Section: Methodsmentioning

confidence: 99%

Layer Positioning of Late-Born Cortical Interneurons Is Dependent on Reelin But Not p35 Signaling

Hammond

Gunnersen

et al. 2006

J. Neurosci.

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“…Reeler homozygous mutant mice were identified by PCR genotyping according to Takahara et al (Takahara et al, 1996). Scrambler mutants were bred as homozygous animals and no genotyping was necessary.…”

Section: Micementioning

confidence: 99%

Reelin signaling is necessary for a specific step in the migration of hindbrain efferent neurons

et al. 2005

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The cytoarchitecture of the hindbrain results from precise and co-ordinated sequences of neuronal migrations. Here, we show that reelin, an extracellular matrix protein involved in neuronal migration during CNS development, is necessary for an early, specific step in the migration of several hindbrain nuclei. We identified two cell populations not previously known to be affected in reeler mutants that show a common migratory defect: the olivocochlear efferent neurons and the facial visceral motor nucleus. In control embryos, these cells migrate first toward a lateral position within the neural tube, and then parallel to the glial cell processes, to a ventral position where they settle close to the pial surface. In reelermutants, the first migration is not affected, but the neurons are unable to reach the pial surface and remain in an ectopic position. Indeed, this is the first evidence that the migration of specific hindbrain nuclei can be divided into two parts: a reelin-independent and a reelin-dependent migration. We also show that reelin is expressed at high levels at the final destination of the migratory process, while the reelin intracellular effector Dab1 was expressed by cell groups that included the two populations affected. Mice mutant at the Dab1 locus, called scrambler, exhibit the same phenotype, a failure of final migration. However, examination of mice lacking both reelin receptors, ApoER2 and VLDLR, did not reveal the same phenotype, suggesting involvement of an additional reelin-binding receptor. In the hindbrain, reelin signaling might alter the adhesive properties of efferent neurons and their ability to respond to directional cues, as has been suggested for the migration of olfactory bulb precursors.

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“…These observations strongly suggest a role for DNA methylation in the protection of eukaryotic genome from viral and parasitic sequences. The de-silencing of transposable elements affects the genome stability and the expression of genes through different mechanisms including the activation of RNAi pathways [8,44].…”

Section: Cpg Dinucleotides Location and Func-tionmentioning

confidence: 99%

Dynamic and reversibility of heterochromatic gene silencing in human disease

et al. 2005

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In eukaryotic organisms cellular fate and tissue specific gene expression are regulated by the activity of proteins known as transcription factors that by interacting with specific DNA sequences direct the activation or repression of target genes. The post genomic era has shown that transcription factors are not the unique key regulators of gene expression. Epigenetic mechanisms such as DNA methylation, post-translational modifications of histone proteins, remodeling of nucleosomes and expression of small regulatory RNAs also contribute to regulation of gene expression, determination of cell and tissue specificity and assurance of inheritance of gene expression levels. The relevant contribution of epigenetic mechanisms to a proper cellular function is highlighted by the effects of their deregulation that cooperate with genetic alterations to the development of various diseases and to the establishment and progression of tumors.

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Dysfunction of the Orleans reeler gene arising from exon skipping due to transposition of a full-length copy of an active L1 sequence into the skipped exon

Cited by 96 publications

References 24 publications

Layer Positioning of Late-Born Cortical Interneurons Is Dependent on Reelin But Not p35 Signaling

Layer Positioning of Late-Born Cortical Interneurons Is Dependent on Reelin But Not p35 Signaling

Reelin signaling is necessary for a specific step in the migration of hindbrain efferent neurons

Dynamic and reversibility of heterochromatic gene silencing in human disease

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