SDF1 Reduces Interneuron Leading Process Branching through Dual Regulation of Actin and Microtubules

Abstract

Normal cerebral cortical function requires a highly ordered balance between projection neurons and interneurons. During development these two neuronal populations migrate from distinct progenitor zones to form the cerebral cortex, with interneurons originating in the more distant ganglionic eminences. Moreover, deficits in interneurons have been linked to a variety of neurodevelopmental disorders underscoring the importance of understanding interneuron development and function. We, and others, have identified SDF1 signaling as one important modulator of interneuron migration speed and leading process branching behavior in mice, although how SDF1 signaling impacts these behaviors remains unknown. We previously found SDF1 inhibited leading process branching while increasing the rate of migration. We have now mechanistically linked SDF1 modulation of leading process branching behavior to a dual regulation of both actin and microtubule organization. We find SDF1 consolidates actin at the leading process tip by de-repressing calpain protease and increasing proteolysis of branched-actin-supporting cortactin. Additionally, SDF1 stabilizes the microtubule array in the leading process through activation of the microtubule-associated protein doublecortin (DCX). DCX stabilizes the microtubule array by bundling microtubules within the leading process, reducing branching. These data provide mechanistic insight into the regulation of interneuron leading process dynamics during neuronal migration in mice and provides insight into how cortactin and DCX, a known human neuronal migration disorder gene, participate in this process.

Thalamo-cortical axons regulate the radial dispersion of neocortical GABAergic interneurons

“…Calpain substrates include many cytoskeletal and signaling proteins and there is abundant evidence linking calpains to the regulation of cell migration, although to date mainly in non-neuronal cells (Franco and Huttenlocher, 2005). Calpain activity has been shown to contribute to the regulation of leading process branching in cultured cortical interneurons (Lysko et al, 2014), one of the key steps in tangential to radial orientation switch. Our studies show that pharmacological blockade of calpain increases KCC2 expression in cortical GABAergic interneurons and hampers the radial dispersion.…”

Differential Mitochondrial Requirements for Radially and Non-radially Migrating Cortical Neurons: Implications for Mitochondrial Disorders

“…Explant and slice cultures were generated from the indicated embryonic day mouse pups as previously described (Lysko et al, 2011; Lysko et al, 2014). …”

“…In contrast, cortical INs take a circuitous path from their origin in the subcortical ganglionic eminences. Along the way, migrating INs frequently pause, change direction, and exhibit extensive branching dynamics of the leading process (Bellion et al, 2005; Lysko et al, 2011, 2014; Polleux et al, 2002). …”

Genetics and mechanisms leading to human cortical malformations

“…The Sdf1 signaling pathway leads to the activation of the calpain protease which cleaves cortactin, reducing Arp2/3 activity, consolidating the actin network and leading to a reduced branch lifetime. Sdf1 signaling was however also shown to activate Dcx, favorising binding and bundling of MTs, stabilizing the MT array and reducing neuronal branches [115]. In addition to bundling MTs in processes, Dcx influences nuclear movement and also promotes MT elongation [89,90,94,97,116].…”