Elsevier

Neuroscience Research

Volume 86, September 2014, Pages 50-58
Neuroscience Research

Review article
How does Reelin control neuronal migration and layer formation in the developing mammalian neocortex?

https://doi.org/10.1016/j.neures.2014.06.004Get rights and content

Highlights

  • Reelin controls terminal translocation via activation of cell adhesion molecules.

  • Reelin-dependent Dab1 degradation is involved in the migration stop.

  • Reelin-dependent inside-out neuronal positioning is established within the PCZ.

  • Reelin signaling may change the cell adhesiveness for proper neuronal layers.

Abstract

The mammalian neocortex has a laminar structure that develops in a birth-date-dependent “inside-out” pattern. Its layered structure is established by neuronal migration accompanied by sequential changes in migratory mode regulated by several signaling cascades. Although Reelin was discovered about two decades ago and is one of the best known molecules that is indispensable to the establishment of the “inside-out” neuron layers, the cellular and molecular functions of Reelin in layer formation are still largely unknown. In this review article, we summarize our recent understanding of Reelin's functions during neuronal migration. Reelin acts in at least two different steps of neuronal migration: the final step of neuronal migration (somal/terminal translocation) just beneath the marginal zone (MZ) and the regulation of cell polarity step when the neurons change their migratory mode from multipolar migration to locomotion. During the translocation mode, Reelin activates integrin α5β1 through an intracellular pathway that triggers the translocation and activates N-cadherin in concert with the nectin-afadin system. Reelin is also involved in the termination of neuronal migration by degrading Dab1 via the SOCS7-Cullin5-Rbx2 system, and Reelin has been found to induce the birth-date-dependent neuronal aggregation in vivo. Based on these findings, we hypothesize that the molecular function of Reelin during neuronal migration is to control cell-adhesiveness during development by regulating the expression/activation of cell adhesion molecules.

Section snippets

Reelin controls the “inside-out” arrangement of neurons in the mammalian cerebral cortex

The mammalian cerebral cortex has a 6-layer structure that serves as the fundamental basis for higher brain functions (Rakic, 2009). The neurons that compose the layers are arranged in a birth-date-dependent “inside-out” manner in which the late-born neurons located more superficially than the early-born neurons. Since this “inside-out” arrangement of neurons in the cerebral cortex is not observed in other vertebrates, it is thought that this arrangement has allowed expansion of the neocortex

Reelin signaling regulates the terminal translocation mode of neuronal migration by activating several cell adhesion molecules

To understand the role of Reelin signaling for neuronal migration in vivo, Olson et al. established knockdown vectors for Dab1 and introduced them into migrating neurons by in utero EP (Olson et al., 2006). They introduced Dab1-knockdown vectors into the future layer II/III neurons, and when they examined the cell positions after neuronal migration was complete, they found that the Dab1 knockdown neurons were located slightly deeper (∼40 μm from the top of the CP) than the control neurons,

Reelin signaling is involved in the termination of neuronal migration through degradation of Dab1

Although Reelin-dependent terminal translocation is an essential process for neuronal layering, it is noteworthy that the translocating neurons complete their migration just beneath the MZ and never enter it. The authors of previous studies have proposed that Reelin acts as a stop signal for neuronal migration by inducing detachment of neurons from radial glial fibers (Dulabon et al., 2000). However, several findings seem to have undermined this “stop signal” model. Magdaleno et al. established

“Deep” Reelin regulates migratory behaviors even before migrating neurons enter the CP

Although most of the Reelin protein is produced by Cajal-Retzius cells in the MZ, previous reports have repeatedly shown evidence of the presence of a small amount of Reelin in the lower IZ/SVZ (Yoshida et al., 2006, Uchida et al., 2009). The precise source of this “deep” Reelin remains to be elucidated, but a recent study provided compelling evidence that functional Reelin receptors are also present in the early/premigratory neurons. By using fusion proteins of the central fragments of Reelin

Reelin induces neuronal aggregation in a birth-date-dependent “inside-out” manner

When the radially migrating neurons arrive beneath the MZ and come into contact with high amount of Reelin in the MZ, they undergo various significant morphological changes in addition to the transition to the terminal translocation mode. Migrating neurons develop apical dendrites and start to express a large number of specific genes (Tachikawa et al., 2008), and they accumulate beneath the MZ (Ajioka and Nakajima, 2005), suggesting that they start to develop the proper layer structure.

Hypothetical model and conclusion

In this review article we have discussed the cellular and molecular mechanisms of Reelin's involvement in neuronal layer formation in the mammalian cerebral cortex. Reelin acts in different places: a small amount of deep Reelin acts in the lower IZ/SVZ and a large amount of Reelin acts in the MZ. The deep Reelin in the lower IZ/SVZ regulates the cell orientation of multipolar neurons toward the pial surface (Jossin and Cooper, 2011), and the Reelin in the MZ regulates several aspects of

Acknowledgements

We thank Dr. Yuki Hirota for valuable discussions. This work was supported by grants from the Strategic Research Program for Brain Sciences (“Understanding of molecular and environmental bases for brain health”) (10036057), and the Grant-in-Aid for Scientific Research of the Ministry of Education, Culture, Sports, Science, and Technology of Japan (22111004, 25640039, 25116522, 26430075), and Keio Gijuku Academic Development Funds.

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