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

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 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.

Clusterin Is a Ligand for Apolipoprotein E Receptor 2 (ApoER2) and Very Low Density Lipoprotein Receptor (VLDLR) and Signals via the Reelin-signaling Pathway

“…Phosphorylated Dab1 acts as a signaling platform binding a variety of proteins involved in further down-stream signaling events (40). A central knot in this Reelin signaling network is the activation of PI3K (8), which leads to the phosphorylation of PKB/Akt (41) and activation of cofilin via LIMK1 (11).…”

Signaling by the Extracellular Matrix Protein Reelin Promotes Granulosa Cell Proliferation in the Chicken Follicle

“…2C, lane 1)) most likely results from a protein expressed by 3T3 fibroblasts incidentally cross-reacting with this antibody because earlier experiments using 3T3 cells clearly showed that Dab1 is not expressed by these cells (34). To verify this result, we performed the same Western blot analysis using an antibody specific for chicken Dab1-E (33), and, as demonstrated in Fig. 2C, lanes 4-6, this antibody only reacts with the Dab1-E-fusion protein.…”

“…The downstream primer specific for the E form is located in exon 9a, which is only present in the transcript for the E variant. The downstream primer specific for the L form is located in exon 8, which is absent from the E variant (33). Both primer pairs produced the specific product corresponding to transcripts for Dab1-E and Dab1-L (verified by sequencing) with mRNA from follicles at different stages of development and granulosa cells.…”

“…5A). In the mammalian brain, phosphorylated Dab1 acts as a signaling platform, binding a variety of proteins involved in further down-stream signaling events (33). A central knot in this Reelin signaling network is the activation of PI3K (35), which leads to the phosphorylation of protein kinase B/Akt (36).…”

Reciprocal Regulation of Very Low Density Lipoprotein Receptors (VLDLRs) in Neurons by Brain-derived Neurotrophic Factor (BDNF) and Reelin

“…Disturbed Reelin signaling has also been associated with neurological diseases such as Alzheimer disease, epilepsy, and schizophrenia (7)(8)(9)(10). Interaction of Reelin with VLDLRs at the cell surface induces signaling and tyrosine phosphorylation of the protein Dab1 (Disabled-1) via the Src family of kinases (11)(12)(13). Phosphorylated Dab1 then transmits the Reelin signal into the cell and influences the cytoskeleton and the expression of specific genes (9,13,14).…”