JNK signaling is required for proper tangential migration and laminar allocation of cortical interneurons

Abstract

The precise migration of cortical interneurons is essential for the formation and function of cortical circuits, and disruptions to this key developmental process are implicated in the etiology of complex neurodevelopmental disorders, including schizophrenia, autism and epilepsy. We have recently identified the Jun N-terminal kinase (JNK) pathway as an important mediator of cortical interneuron migration in mice, regulating the proper timing of interneuron arrival into the cortical rudiment. In the current study, we demonstrate a vital role for JNK signaling at later stages of corticogenesis, when interneurons transition from tangential to radial modes of migration. Pharmacological inhibition of JNK signaling in ex vivo slice cultures caused cortical interneurons to rapidly depart from migratory streams and prematurely enter the cortical plate. Similarly, genetic loss of JNK function led to precocious stream departure ex vivo, and stream disruption, morphological changes and abnormal allocation of cortical interneurons in vivo. These data suggest that JNK signaling facilitates the tangential migration and laminar deposition of cortical interneurons, and further implicates the JNK pathway as an important regulator of cortical development.

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

“…However, when we analyzed nucleokinesis, the kinetics of movement were opposite: JNK-inhibited cells completed nucleokinesis at slower rates, whereas cTKO cells completed at faster rates. These data imply that cortical interneuron migration is dependent on both intrinsic and extrinsic requirements for JNK signaling, as suggested from recent in vivo and ex vivo experiments (Myers et al, 2020). While the exact mechanisms that cortical interneurons utilize to navigate their environment remain to be fully elucidated, we have found that JNK signaling exerts fine-tune control over cell biological processes required for proper interneuron migration.…”

“…c-Jun NH 2 -terminal kinase (JNK) signaling is required for the initial entry of cortical interneurons into the cortical rudiment and the tangential progression of interneurons in migratory streams (Myers et al, 2020; Myers et al, 2014). In the current study, we examined the role that JNK plays in the migratory dynamics of individual interneurons.…”

“…Disruption to JNK signaling has been linked to aberrant migration of excitatory cortical neurons (Hirai et al, 2006; Wang et al, 2007; Westerlund et al, 2011; Yamasaki et al, 2011; Zhang et al, 2016) as well as cognitive disorders in humans (Kunde et al, 2013; McGuire et al, 2017). More recently, we found that JNK signaling controls the timing of interneuron entry into the cerebral cortex, as well as the formation and maintenance of tangential streams of cortical interneurons (Myers et al, 2020; Myers et al, 2014), but the role that JNK plays in the migratory properties of individual cortical interneurons has not been examined.…”

Involvement of JNK1 in Neuronal Polarization During Brain Development

“…These observations were achieved by labelling interneurons with Green Fluorescence Protein (GFP) under control of the Distal-less Homeobox-(Dlx5/6) promoter and recording live brain slices. Jnk1 -/mice showed the most dominant effect, but double Jnk1 -/-Jnk2 -/+ and tripe conditional Jnk flox/flox Jnk2 -/-Jnk3 -/knock-out mice show exacerbated migratory defects at E13 [108,109].…”

“…Remarkably, in the late stages of development (E15), migratory defects are partially rescued by an unknown mechanism, and only cortical malformations and mispositioned interneurons are observed [108].…”