Reelin-Disabled-1 signaling in neuronal migration: splicing takes the stage
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Cellular and Molecular Life Sciences
REVIEW
Reelin-Disabled-1 signaling in neuronal migration: splicing takes the stage Zhihua Gao • Roseline Godbout
Received: 25 July 2012 / Revised: 19 August 2012 / Accepted: 13 September 2012 / Published online: 28 September 2012 Ó Springer Basel 2012
Abstract 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 domaincontaining 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. Keywords Neuronal migration Reelin Disabled-1 Alternative splicing Tyrosine phosphorylation SH2 domain
Introduction The precise positioning of neurons within the brain remains an important question in developmental neurobiology. There is accumulating evidence supporting key roles for molecules such as Cdk5, Lis1, Reelin and n-cofilin in regulating neuronal migration, resulting in the formation of laminated structures [1–5]. The Reelin-Disabled-1 (Dab1) signaling pathway in particular has a well-established role in regulating the ‘‘inside–out’’ lamination of the cerebral cortex [5–7]. Recent advances provide important insight into how Reelin induces the activation of intracellular signaling cascades and rearrangement of cytoskeleton to guide neuronal migration. Yet, how these intracellular signaling events are orchestrated in a temporal and spatial manner and how Reelin coordinates the movement of individual subpopulation of neurons to achieve ordered assembly in the brain remains poorly understood. Here, we review recent publications that address Reelin signaling in the regulation of neuronal migration. We focus on the role of developmentally-regulated Dab1 alternative splicing in modulating the activity of the Reelin pathway to coordinate neuronal migration.
Neuronal migration during cortical development
Z. Gao (&) R. Godbout (&) Department of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada e-mail: [email protected] R. Godbout e-mail: [email protected]
In the cerebral cortex, neuronal migration begins when the first wave of early-born neurons leaves the ventricular zone (VZ) to establish the preplate [8, 9]. The second wave of early-born neurons then split the preplate to form the
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