Abstract
GSK-3 is an essential mediator of several signaling pathways that regulate cortical development. We therefore created conditional mouse mutants lacking both GSK-3α and GSK-3β in newly born cortical excitatory neurons. Gsk3-deleted neurons expressing upper layer markers exhibited striking migration failure in all areas of the cortex. Radial migration in hippocampus was similarly affected. In contrast, tangential migration was not grossly impaired after Gsk3 deletion in interneuron precursors. Gsk3-deleted neurons extended axons and developed dendritic arbors. However, the apical dendrite was frequently branched while basal dendrites exhibited abnormal orientation. GSK-3 regulation of migration in neurons was independent of Wnt/β-catenin signaling. Importantly, phosphorylation of the migration mediator, DCX, at ser327, and phosphorylation of the semaphorin signaling mediator, CRMP-2, at Thr514 were markedly decreased. Our data demonstrate that GSK-3 signaling is essential for radial migration and dendritic orientation and suggest that GSK-3 mediates these effects by phosphorylating key microtubule regulatory proteins.DOI: http://dx.doi.org/10.7554/eLife.02663.001.
Highlights
Glycogen synthase kinase (GSK-3) α and β are serine/threonine kinases that act as key downstream regulators in multiple signaling pathways, including Wnt/β-catenin, receptor tyrosine kinase (RTK)/PI3K, and Sonic hedgehog (Shh) (Kaidanovich-Beilin et al, 2012)
A GSK-3 phosphomimetic Collapsin response mediator protein-2 (CRMP-2) can rescue migration defects associated with knockdown of the semaphorin signaling mediator, α2-chimaerin (Ip et al, 2012). These findings suggest that inhibition of CRMP2 phosphorylation at Thr514 in Gsk3bloxp/loxp: Neurod6-Cre mice (Gsk3)-deleted neurons may partially explain the migration and dendritic orientation abnormalities we have observed
We have demonstrated a key cell autonomous role for GSK-3 signaling in regulating radial migration and dendritic orientation of cortical excitatory neurons
Summary
Glycogen synthase kinase (GSK-3) α and β are serine/threonine kinases that act as key downstream regulators in multiple signaling pathways, including Wnt/β-catenin, receptor tyrosine kinase (RTK)/PI3K, and Sonic hedgehog (Shh) (Kaidanovich-Beilin et al, 2012). Not invariably, GSK-3s function as negatively acting kinases by inhibiting the functions of substrates at baseline. Inhibition is relieved via signaling pathways that engage GSK-3 (Doble and Woodgett, 2003; Kaidanovich-Beilin and Woodgett, 2011). For most GSK-3 substrates, phosphorylation by another kinase near the GSK-3 site (‘priming’) is required for, or enhances, GSK-3 substrate phosphorylation (Cohen and Frame, 2001; Doble and Woodgett, 2003; Kaidanovich-Beilin and Woodgett, 2011). Priming kinases for GSK-3 substrates include cyclin dependent kinase-5 (cdk5), a kinase that is known to regulate important neurodevelopmental events like radial migration (Tanaka et al, 2004; Cole et al, 2006; Li et al, 2006; Xie et al, 2006)
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