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JNK signaling controls branching, nucleokinesis, and positioning of centrosomes and primary cilia in migrating cortical interneurons

Skye E. Smith, Nicholas K. Coker, View ORCID ProfileEric S. Tucker
doi: https://doi.org/10.1101/2020.01.30.927855
Skye E. Smith
Department of Neuroscience, West Virginia University School of Medicine, Morgantown, WV 26506
Biochemistry and Molecular Biology Graduate Program, West Virginia University School of Medicine, Morgantown, WV 26506
Rockefeller Neuroscience Institute, West Virginia University School of Medicine, Morgantown, WV 26506
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Nicholas K. Coker
Department of Neuroscience, West Virginia University School of Medicine, Morgantown, WV 26506
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Eric S. Tucker
Department of Neuroscience, West Virginia University School of Medicine, Morgantown, WV 26506
Rockefeller Neuroscience Institute, West Virginia University School of Medicine, Morgantown, WV 26506
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  • ORCID record for Eric S. Tucker
  • For correspondence: etucker@hsc.wvu.edu
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ABSTRACT

Aberrant migration of inhibitory interneurons can alter the formation of cortical circuitry and lead to severe neurological disorders including epilepsy, autism, and schizophrenia. However, mechanisms involved in directing the migration of these cells remain incompletely understood. In the current study, we used live-cell confocal microscopy to explore the mechanisms by which the c-Jun NH2-terminal kinase (JNK) pathway coordinates leading process branching and nucleokinesis, two cell biological processes that are essential for the guided migration of cortical interneurons. Pharmacological inhibition of JNK signaling disrupts the kinetics of leading process branching, rate and amplitude of nucleokinesis, and leads to the rearward mislocalization of the centrosome and primary cilium to the trailing process. Genetic loss of Jnk from interneurons corroborates our pharmacological observations and suggests that important mechanics of interneuron migration depend on the intrinsic activity of JNK. These findings suggest that JNK signaling regulates leading process branching, nucleokinesis, and the trafficking of centrosomes and cilia during interneuron migration, and further implicates JNK signaling as an important mediator of cortical development.

Summary Statement Loss of JNK signaling reduces growth cone branching frequency, limits interstitial side branch duration, alters rate and amplitude of nucleokinesis, and mislocalizes centrosomes and primary cilia in migrating cortical interneurons.

  • SYMBOLS AND ABBREVIATIONS

    MGE
    Medial ganglionic eminence
    CGE
    Caudal ganglionic eminence
    JNK
    c-Jun NH2-terminal kinase
    Dcx
    Doublecortin
    Cetn2-mCherry
    Centrin2-mCherry
    Dlx5/6-CIE
    Dlx5/6-Cre-IRES-EGFP
    cTKO
    conditional Jnk triple knockout
    WT
    Wild type
    MAPK
    mitogen-activated protein kinase
    cHBSS
    complete Hank’s Balanced Salt Solution
    Shh
    Sonic hedgehog
    E14.5
    Embryonic day 14.5
    μ
    Micro
    Cxcr4
    C-X-C motif chemokine receptor 4
    ErbB4
    erb-b2 receptor tyrosine kinase 4
    5-Htr6
    Serotonin receptor 6
    s.e.m.
    standard error of the mean
  • Copyright 
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    Posted January 31, 2020.
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    JNK signaling controls branching, nucleokinesis, and positioning of centrosomes and primary cilia in migrating cortical interneurons
    Skye E. Smith, Nicholas K. Coker, Eric S. Tucker
    bioRxiv 2020.01.30.927855; doi: https://doi.org/10.1101/2020.01.30.927855
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    JNK signaling controls branching, nucleokinesis, and positioning of centrosomes and primary cilia in migrating cortical interneurons
    Skye E. Smith, Nicholas K. Coker, Eric S. Tucker
    bioRxiv 2020.01.30.927855; doi: https://doi.org/10.1101/2020.01.30.927855

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