AMP-activated protein kinase regulates cytoplasmic dynein behavior and contributes to neuronal migration in the developing neocortex

Development. 2020 Jul 15;147(14):dev187310. doi: 10.1242/dev.187310.

Abstract

The microtubule motor cytoplasmic dynein contributes to radial migration of newborn pyramidal neurons in the developing neocortex. Here, we show that AMP-activated protein kinase (AMPK) mediates the nucleus-centrosome coupling, a key process for radial neuronal migration that relies on dynein. Depletion of the catalytic subunit of AMPK in migrating neurons impairs this coupling as well as neuronal migration. AMPK shows overlapping subcellular distribution with cytoplasmic dynein and the two proteins interact with each other. Pharmacological inhibition or activation of AMPK modifies the phosphorylation states of dynein intermediate chain (DIC) and dynein functions. Furthermore, AMPK phosphorylates DIC at Ser81. Expression of a phospho-resistant mutant of DIC retards neuronal migration in a similar way to AMPK depletion. Conversely, expression of the phospho-mimetic mutant of DIC alleviates impaired neuronal migration caused by AMPK depletion. Thus, AMPK-regulated dynein function via Ser81 DIC phosphorylation is crucial for radial neuronal migration.

Keywords: AMP-activated protein kinase; Developing neocortex; Dynein; Neuronal migration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / antagonists & inhibitors
  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Cell Movement
  • Cell Nucleus / metabolism
  • Centrosome / metabolism
  • Cytoplasmic Dyneins / genetics
  • Cytoplasmic Dyneins / metabolism*
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / metabolism
  • Embryonic Development
  • Mice
  • Mice, Inbred ICR
  • Mutagenesis, Site-Directed
  • Neocortex / metabolism*
  • Neurons / cytology
  • Neurons / metabolism
  • PAX6 Transcription Factor / metabolism
  • Phosphorylation
  • RNA Interference
  • RNA, Small Interfering / metabolism

Substances

  • PAX6 Transcription Factor
  • Pax6 protein, mouse
  • RNA, Small Interfering
  • AMPK alpha1 subunit, mouse
  • AMPK alpha2 subunit, mouse
  • AMP-Activated Protein Kinases
  • Cytoplasmic Dyneins