Cdk5 phosphorylation of ErbB4 is required for tangential migration of cortical interneurons.
Bottom Line: Interneuron dysfunction in humans is often associated with neurological and psychiatric disorders, such as epilepsy, schizophrenia, and autism.Some of these disorders are believed to emerge during brain formation, at the time of interneuron specification, migration, and synapse formation.This finding identifies Cdk5 as a crucial signaling factor in cortical interneuron development in mammals.
Affiliation: Department of Cell and Developmental Biology, University College London, London WC1 6BT, UK.Show MeSH
Related in: MedlinePlus
Mentions: The signaling mechanisms by which ErbB4 exerts its functions in cell migration are only partly understood. Unlike other members of ErbB receptor family, this gene is subject to differential promoter usage and alternative splicing (Junttila et al. 2000; Sundvall et al. 2008). On the one hand, extracellular juxtamembrane (JM) isoforms are either sensitive (JMa) or resistant (JMb) to proteolytic cleavage (Fig. 2A). On the other, cytoplasmic isoforms, Cyt1 and Cyt2, differ by the presence (Cyt1) or absence (Cyt2) of a binding site for PI 3-kinase (tyrosine Y1056; Fig. 2A); the coupling of Cyt1 with PI3-kinase/Akt pathway stimulates chemotaxis (Kainulainen et al. 2000; Gambarotta et al. 2004). Here, we observed temporal and spatial regulation of ErbB4 isoform expression in forebrain interneurons (GFPGAD67(+); Fig. 2B,C). Importantly, GFPGAD67(+) cells in the GE, but not in the Cx, at E13.5, lacked expression of the PI3-kinase-binding/chemotaxis-mediating ErbB4 isoform (Cyt1; Fig. 2C). Accordingly, by using phosphorylation state-specific ab, we found that ErbB4 was significantly phosphorylated on Cyt1-specific Y1056 in the Cx, but not in the lateral (L) GE or MGE (Fig. 2D). Together, these findings suggest that ErbB4/PI3-kinase signaling may be important for migration of interneurons toward and within the Cx (Fig. 2E).Figure 2.
Affiliation: Department of Cell and Developmental Biology, University College London, London WC1 6BT, UK.