C-Jun NH2-terminal kinase signaling controls cellular mechanisms of guided cortical interneuron migration

Abstract

The cerebral cortex is an intricately organized brain structure responsible for high-level functions including sensory perception, movement, memory, language, and cognition. During corticogenesis, cortical excitatory neurons and inhibitory interneurons migrate from their respective progenitor zones into the developing cerebral cortex, deposit in the correct cortical layer, and establish connections with their appropriate synaptic partners. The balance between excitation and inhibition is critical for cortical circuitry development and function. Aberrant migration of inhibitory interneurons can alter the formation of cortical circuitry and lead to several neurodevelopmental disorders including epilepsy, autism spectrum disorder, and schizophrenia. Therefore, elucidating the mechanisms responsible for inhibitory interneuron migration will provide greater insight into the development of these diseases. This dissertation explores the role of c-Jun NH2-terminal kinase (JNK) signaling pathway in the cellular mechanisms required for the guided migration of cortical interneurons. In Chapter 2, I used live-cell confocal microscopy to explore the mechanisms by which JNK activity coordinates two cell biological processes that are essential for the guided migration of cortical interneurons: nucleokinesis and leading process branching. I found that pharmacological inhibition and genetic ablation of JNK-signaling in cortical interneurons impairs the kinetics of nucleokinesis. Moreover, JNK signaling controls the subcellular localization of the centrosome and primary cilium, two organelles involved in nucleokinesis. To orient their direction of migration, cortical interneurons extend and retract leading process branches to respond to chemotactic guidance cues present in their environments. Both pharmacological inhibition and genetic removal of JNK disrupted the stability of leading process branches, resulting in decreased frequency of growth cone splits and the shortened duration of interstitial side branches. In Chapter 3, I explored the role of JNK signaling in nucleokinesis of interneurons migrating in different substrate and topographical environments and found that cortical interneurons have an intrinsic requirement for JNK signaling during nucleokinesis regardless of substrate environment. Moreover, I found that interneurons can use nanoscale features in their environment to orient their direction of migration. Additionally, cortical interneurons aligned on a nanopattern topography have a highly polarized subcellular localization of doublecortin, a substrate of JNK involved in microtubule stability. Together, these are the first studies examining the role of JNK signaling in the cellular mechanisms controlling cortical interneuron migration and provide novel insight into the roles of JNK in cortical inhibitory interneuron development. Future efforts should be aimed at unraveling the mechanism through which JNK controls interneuron migration by exploring JNK’s role in cytoskeletal dynamics