Ectopic Reelin Induces Neuronal Aggregation with a Normal Birthdate-Dependent “Inside-Out” Alignment in the Developing Neocortex

Kubo, Ken Ichiro; Honda, Takao; Tomita, Kenji; Sekiné, Kazuki; Ishii, Kazuhiro; Uto, Asuka; Kobayashi, K.; Tabata, Hidenori; Nakajima, Kazunori

doi:10.1523/jneurosci.0486-10.2010

Cited by 67 publications

(82 citation statements)

References 49 publications

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“…1 F-F′′ and H-H′′) and neuronal nuclei (NeuN) (Fig. S2 A and B), which is consistent with our previous finding that ectopically overexpressed Reelin caused aggregation of migrating neurons in vivo (15). It is worthy of note, however, that some nestinpositive and paired box protein 6 (Pax6)-positive neural progenitor cells [radial glial cells (RGCs)] were also incorporated into these aggregates.…”

Section: Resultssupporting

confidence: 90%

“…In regard to the adhesion molecule mediating the Reelin-dependent neuronal aggregation, we thought that N-cadherin might be a good candidate because N-cadherin is present in abundance in the cortical MZ (27). Therefore, we examined whether N-cadherin could also be detected when the migrating neurons aggregated in vivo in response to ectopically overexpressed Reelin in the developing neocortex (15). As expected, immunohistochemical examination revealed strong detection of N-cadherin in the central cell body-sparse, dendrite-rich, MZ-like region of the ectopic aggregates in vivo (12) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Our recent investigation demonstrated that ectopically overexpressed Reelin in the developing neocortex caused aggregation of the migrating neurons in the CP in vivo (15). However, it remained unclear as to whether Reelin directly strengthened adhesion among neurons or indirectly caused aggregation of the neurons by, for example, causing the local cellular environment to repel the migrating neurons.…”

Section: Discussionmentioning

confidence: 99%

“…In recently carried out studies, we revealed that ectopic expression of Reelin by in utero electroporation caused neuronal aggregation in the developing mouse neocortex (15)(16)(17). In addition, we found that immature neurons were densely packed in the outermost region of the developing cortex (i.e., beneath the MZ), which is termed the primitive cortical zone (PCZ) (18), supporting the notion that Reelin may somehow be involved in the aggregation of migrating neurons beneath the MZ in vivo.…”

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confidence: 99%

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Reelin transiently promotes N-cadherin–dependent neuronal adhesion during mouse cortical development

Matsunaga

Noda

Murakawa

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Reelin is an essential glycoprotein for the establishment of the highly organized six-layered structure of neurons of the mammalian neocortex. Although the role of Reelin in the control of neuronal migration has been extensively studied at the molecular level, the mechanisms underlying Reelin-dependent neuronal layer organization are not yet fully understood. In this study, we directly showed that Reelin promotes adhesion among dissociated neocortical neurons in culture. The Reelin-mediated neuronal aggregation occurs in an N-cadherin-dependent manner, both in vivo and in vitro. Unexpectedly, however, in a rotation culture of dissociated neocortical cells that gradually reaggregated over time, we found that it was the neural progenitor cells [radial glial cells (RGCs)], rather than the neurons, that tended to form clusters in the presence of Reelin. Mathematical modeling suggested that this clustering of RGCs could be recapitulated if the Reelin-dependent promotion of neuronal adhesion were to occur only transiently. Thus, we directly measured the adhesive force between neurons and N-cadherin by atomic force microscopy, and found that Reelin indeed enhanced the adhesiveness of neurons to N-cadherin; this enhanced adhesiveness began to be observed at 30 min after Reelin stimulation, but declined by 3 h. These results suggest that Reelin transiently (and not persistently) promotes N-cadherin-mediated neuronal aggregation. When N-cadherin and stabilized β-catenin were overexpressed in the migrating neurons, the transfected neurons were abnormally distributed in the superficial region of the neocortex, suggesting that appropriate regulation of N-cadherin-mediated adhesion is important for correct positioning of the neurons during neocortical development.T he mammalian neocortex is highly organized into six neuronal layers. This laminar structure is responsible for the complex motor, sensory, and cognitive functions of the mammalian brain (1). Neuronal migration plays an important role in the establishment of this layered structure. Cortical neurons are generated within the ventricular zone (VZ) or subventricular zone (SVZ), and migrate along radial fibers toward the pial surface. Newly born excitatory neurons migrate radially into the cortical plate (CP) past the neurons born earlier, resulting in a birth date-dependent "inside-out" alignment of the neurons in the CP (2-4).Reelin is a glycoprotein that is secreted by the Cajal-Retzius cells in the marginal zone (MZ) of the cortex during neocortical development (5-7). This glycoprotein is essential for establishment of the aforementioned birth date-dependent layered structure of the neocortex, because the CP neurons show an almost inverted alignment in the neocortex of the Reelindeficient, reeler mice. In addition, neurons born at the same time tend to be distributed broadly and not to form clear layers in the reeler cortex (8, 9). Although extensive studies, including at the molecular level, have been conducted to determine the role of Reelin in neuronal migration i...

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Reelin transiently promotes N-cadherin–dependent neuronal adhesion during mouse cortical development

Matsunaga

Noda

Murakawa

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…In fact, ectopic expression of Reelin in the VZ rescues the subplate split phenotype in the reeler cortex and cortical slice cultures [63][64]. Ectopic Reelin also induces neuronal aggregation generating an "inside-out" pattern for cortical neurons in the developing cerebral cortex [65]. Moreover, depletion of Dab1 by knockdown or tissuespecific genetic ablation in the cortex delays neuronal migration [42,66], whereas introduction of wild-type Dab1 into Dab1 −/− cortex promotes the migration of neurons out of the ventricular zone [59].…”

Section: Detach and Stop Detach And Go -Models For Reelin Signaling mentioning

confidence: 99%

Reelin-Disabled-1 signaling in neuronal migration: splicing takes the stage

Gao

Godbout

2012

Cell. Mol. Life Sci.

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Reelin-Disabled-1 (Dab1) signaling has a well-established role in regulating neuronal migration during brain development. Binding of Reelin to its receptors induces Dab1 tyrosine phosphorylation. Tyrosine-phosphorylated Dab1 recruits a wide range of SH2 domain-containing proteins and activates multiple signaling cascades, resulting in cytoskeleton remodeling and precise neuronal positioning. In this review, we summarize recent progress in the Reelin-Dab1 signaling field. We focus on Dab1 alternative splicing as a mechanism for modulating the Reelin signal in developing brain. We suggest that correct positioning of neurons in the developing brain is at least partly controlled by alternatively-spliced Dab1 isoforms that differ in the number and type of tyrosine phosphorylation motifs that they contain. We propose a model whereby different subsets of SH2 domain-containing proteins are activated by different Dab1 isoforms, resulting in coordinated migration of neurons.

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Neuronal Migration: An Overview of Modes, Molecular Mechanisms and Model Systems

Icha

Norden

2014

Encyclopedia of Life Sciences

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A century ago, Santiago Ramón y Cajal had already postulated that neurons born in specific proliferative zones have to migrate to ensure correct neocortical layering. Today we know that neuronal migration is a common phenomenon in many brain regions and that neurons are often born micrometres to centimetres away from the place they fulfil their function. Mutations that lead to defects in neuronal migration can have devastating consequences like lissencephaly, autism and schizophrenia in humans. With these conditions in mind, neuronal migration has been an area of intense research for more than 50 years. Additionally, neuronal migration phenomena are outstanding models to understand basic themes in cell biology. The rodent neocortex has been a very popular system to study different modes of neuronal migration. More recently, additional model tissues and organisms have been examined, which help to further expand our knowledge. The authors provide an overview on different migratory modes and then focus on the cell biology that enables migration in different contexts. They further discuss some experimental challenges that need to be overcome in order to understand neuronal migration in even more depth. Key Concepts: Actomyosin and microtubules play active roles in neuronal migration. Their exact roles depend on cellular context. Endo‐ and exocytosis of adhesion molecules are crucial for cell–cell and cell–substrate adhesion during migration. Extracellular matrix proteins are important guidance cues for neuronal migration. Neuronal migration is a widespread phenomenon in the central nervous system. The advancement of modern light microscopy should be embraced to observe neuronal migration modes in intact developing organism. Two basic modes of migration exist: radial and tangential migration.

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Ectopic Reelin Induces Neuronal Aggregation with a Normal Birthdate-Dependent “Inside-Out” Alignment in the Developing Neocortex

Cited by 67 publications

References 49 publications

Reelin transiently promotes N-cadherin–dependent neuronal adhesion during mouse cortical development

Reelin transiently promotes N-cadherin–dependent neuronal adhesion during mouse cortical development

Reelin-Disabled-1 signaling in neuronal migration: splicing takes the stage

Neuronal Migration: An Overview of Modes, Molecular Mechanisms and Model Systems

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