CDK5-dependent activation of dynein in the axon initial segment regulates polarized cargo transport in neurons

Eva Klinman, Mariko Tokito, Erika L.F. Holzbaur

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

The unique polarization of neurons depends on selective sorting of axonal and somatodendritic cargos to their correct compartments. Axodendritic sorting and filtering occurs within the axon initial segment (AIS). However, the underlying molecular mechanisms responsible for this filter are not well understood. Here, we show that local activation of the neuronal-specific kinase cyclin-dependent kinase 5 (CDK5) is required to maintain AIS integrity, as depletion or inhibition of CDK5 induces disordered microtubule polarity and loss of AIS cytoskeletal structure. Furthermore, CDK5-dependent phosphorylation of the dynein regulator Ndel1 is required for proper re-routing of mislocalized somatodendritic cargo out of the AIS; inhibition of this pathway induces profound mis-sorting defects. While inhibition of the CDK5-Ndel1-Lis1-dynein pathway alters both axonal microtubule polarity and axodendritic sorting, we found that these defects occur on distinct timescales; brief inhibition of dynein disrupts axonal cargo sorting before loss of microtubule polarity becomes evident. Together, these studies identify CDK5 as a master upstream regulator of trafficking in vertebrate neurons, required for both AIS microtubule organization and polarized dynein-dependent sorting of axodendritic cargos, and support an ongoing and essential role for dynein at the AIS.

Original languageEnglish
Pages (from-to)808-824
Number of pages17
JournalTraffic
Volume18
Issue number12
DOIs
StatePublished - Dec 2017

Keywords

  • axon initial segment
  • CDK5
  • dynein
  • Lis1
  • microtubule polarity
  • Ndel1
  • polarized transport

Fingerprint

Dive into the research topics of 'CDK5-dependent activation of dynein in the axon initial segment regulates polarized cargo transport in neurons'. Together they form a unique fingerprint.

Cite this