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








