Cortical Interneurons Require Jnk1 to Enter and Navigate the Developing Cerebral Cortex

Myers, Abigail; Meechan, Daniel W.; Adney, Danielle R.; Tucker, Eric S.

doi:10.1523/jneurosci.4695-13.2014

“…More generally, these different phases of movement can be seen as two different migration strategies: one directed and the other a more exploratory one, both serving different purposes along the course of interneuron displacement. The signals controlling the switch between directed movements and re-orientation are partly understood [9,51,57,[74][75][76]. Our study reveals that a simple change in the geometry of the topography can orient interneurons towards one strategy of movement or the other in vitro.…”

Section: Discussionmentioning

confidence: 79%

Topographical cues control the morphology and dynamics of migrating cortical interneurons

Leclech

¹

,

Renner

²

,

Villard

³

et al. 2019

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In mammalian embryos, cortical interneurons travel long distances among complex threedimensional tissues before integrating into cortical circuits. Several molecular guiding cues involved in this migration process have been identified, but the influence of physical parameters remains poorly understood. In the present study, we have investigated in vitro the influence of the topography of the microenvironment on the migration of primary cortical interneurons released from mouse embryonic explants. We found that arrays of PDMS micro-pillars of 10µm size and spacing, either round or square, influenced both the morphology and the migratory behavior of interneurons. Strikingly, most interneurons exhibited a single and long leading process oriented along the diagonals of the square pillared array, whereas leading processes of interneurons migrating inbetween round pillars were shorter, often branched and oriented in all available directions. Accordingly, dynamic studies revealed that growth cone divisions were twice more frequent in round than in square pillars. Both soma and leading process tips presented forward directed movements within square pillars, contrasting with the erratic trajectories and more dynamic movements observed among round pillars. In support of these observations, long interneurons migrating in square pillars displayed tight bundles of stable microtubules aligned in the direction of migration. Overall, our results show that micron-sized topography provides global spatial constraints promoting the establishment of different morphological and migratory states. Remarkably, these different states belong to the natural range of migratory behaviors of cortical interneurons, highlighting the potential importance of topographical cues in the guidance of these embryonic neurons, and more generally in brain development.

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“…More generally, these different phases of movement can be seen as two different migration strategies: one directed and the other a more exploratory one, both serving different purposes along the course of interneuron displacement. The signals controlling the switch between directed movements and re-orientation remain partly elucidated [9,52,[63][64][65][66]. Our study reveals that a simple change in the geometry of the topography can orient interneurons towards one strategy of movement or the other in vitro.…”

Section: Discussionmentioning

confidence: 78%

Topographical cuescontrol the morphology and dynamics of migrating cortical interneurons

Leclech

¹

,

Renner

²

,

Villard

³

et al. 2018

Preprint

0

View full text Add to dashboard Cite

In mammalian embryos, cortical interneurons travel long distances among complex threedimensional tissues before integrating into cortical circuits. Several molecular guiding cues involved in this migration process have been identified, but the influence of physical parameters remains poorly understood. In the present study, we have investigated in vitro the influence of the topography of the microenvironment on the migration of primary cortical interneurons released from mouse embryonic explants.We found that arrays of 10 µm-sized PDMS micro-pillars, either round or square, influenced both the morphology and the migratory behavior of interneurons. Strikingly, most interneurons exhibited a single and long leading process oriented along the diagonals of the square pillared array, whereas leading processes of interneurons migrating in-between round pillars were shorter, often branched and oriented in all available directions. Accordingly, dynamic studies revealed that growth cone divisions were twice more frequent in round than in square pillars. Both soma and leading process tips presented forward directed movements within square pillars, contrasting with the erratic trajectories and more dynamic movements observed among round pillars. In support of these observations, long interneurons migrating in square pillars displayed tight bundles of stable microtubules aligned in the direction of migration.Overall, our results show that micron-sized topography provides global spatial constraints promoting the establishment of two different morphological and migratory states.Remarkably, both states belong to the natural range of migratory behaviors of cortical interneurons, highlighting the potential importance of topographical cues in the guidance of these embryonic neurons, and more generally in brain development.In this study, we investigated this question using microstructured substrates and demonstrated the high sensitivity of cortical interneurons to the architecture of their environment. Our results revealed that topographical constraints efficiently modulate the migratory behavior of interneurons by controlling cell morphology, branching dynamics and cytoskeletal organization. In particular, by using two shapes of micron-sized pillars, we have been able to select and stabilize in vitro two main migratory behaviors observed in vivo, associated with specific morphologies: non-branched cells with long leading processes showed a directional movement among square pillars, and branched cells with short leading processes displayed a fast, exploratory migration among round pillars. This study therefore provides new insights into the guidance and the biology of these cells. The in vitro model described in this study thus emerges as a new promising tool to control and study interneuron migratory behaviors in physiological or pathological conditions.

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“…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.…”

Section: Resultsmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Se

¹

,

Nk

²

,

Tucker

³

2020

Preprint

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Statement: Loss of JNK signaling reduces growth cone branching frequency, limits 17 interstitial side branch duration, alters rate and amplitude of nucleokinesis, and mislocalizes 18 centrosomes and primary cilia in migrating cortical interneurons. ABSTRACT 34Aberrant migration of inhibitory interneurons can alter the formation of cortical circuitry and lead 35 to severe neurological disorders including epilepsy, autism, and schizophrenia. However, 36 mechanisms involved in directing the migration of these cells remain incompletely understood. 37In the current study, we used live-cell confocal microscopy to explore the mechanisms by which 38 the c-Jun NH 2 -terminal kinase (JNK) pathway coordinates leading process branching and 39 nucleokinesis, two cell biological processes that are essential for the guided migration of cortical 40 interneurons. Pharmacological inhibition of JNK signaling disrupts the kinetics of leading 41 process branching, rate and amplitude of nucleokinesis, and leads to the rearward 42 mislocalization of the centrosome and primary cilium to the trailing process. Genetic loss of Jnk 43 from interneurons corroborates our pharmacological observations and suggests that important 44 mechanics of interneuron migration depend on the intrinsic activity of JNK. These findings 45 suggest that JNK signaling regulates leading process branching, nucleokinesis, and the 46 trafficking of centrosomes and cilia during interneuron migration, and further implicates JNK 47 signaling as an important mediator of cortical development. 48 49 SYMBOLS AND ABBREVIATIONS 50 MGE: Medial ganglionic eminence 51 CGE: Caudal ganglionic eminence 52 JNK: c-Jun NH 2 -terminal kinase 53 Dcx: Doublecortin 54 Cetn2-mCherry: Centrin2-mCherry 55 Dlx5/6-CIE: Dlx5/6-Cre-IRES-EGFP

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Cortical Interneurons Require Jnk1 to Enter and Navigate the Developing Cerebral Cortex

Cited by 33 publications

References 59 publications

Topographical cues control the morphology and dynamics of migrating cortical interneurons

Topographical cues control the morphology and dynamics of migrating cortical interneurons

Topographical cuescontrol the morphology and dynamics of migrating cortical interneurons

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

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