A JIP3-regulated GSK3?/DCX signaling pathway restricts axon branching.

ABSTRACT: Axon branching plays a critical role in establishing the accurate patterning of neuronal circuits in the brain. However, the mechanisms that control axon branching remain poorly understood. Here we report that knockdown of the brain-enriched signaling protein JNK-interacting protein 3 (JIP3) triggers exuberant axon branching and self-contact in primary granule neurons of the rat cerebellar cortex. JIP3 knockdown in cerebellar slices and in postnatal rat pups in vivo leads to the formation of ectopic branches in granule neuron parallel fiber axons in the cerebellar cortex. We also find that JIP3 restriction of axon branching is mediated by the protein kinase glycogen synthase kinase 3? (GSK3?). JIP3 knockdown induces the downregulation of GSK3? in neurons, and GSK3? knockdown phenocopies the effect of JIP3 knockdown on axon branching and self-contact. Finally, we establish doublecortin (DCX) as a novel substrate of GSK3? in the control of axon branching and self-contact. GSK3? phosphorylates DCX at the distinct site of Ser327 and thereby contributes to DCX function in the restriction of axon branching. Together, our data define a JIP3-regulated GSK3?/DCX signaling pathway that restricts axon branching in the mammalian brain. These findings may have important implications for our understanding of neuronal circuitry during development, as well as the pathogenesis of neurodevelopmental disorders of cognition.

SUBMITTER: Bilimoria PM 

PROVIDER: S-EPMC3409248 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature