RACK1 is required for axon guidance and local translation at growth cone point contacts

Abstract

Local translation regulates the formation of appropriate connectivity in the developing nervous system. However, the localization and molecular mechanisms underlying this translation within growth cones is not well understood. Receptor for activated C kinase 1 (RACK1) is a multifunctional ribosomal scaffolding protein that interacts with β-actin mRNA. We recently showed that RACK1 localizes to and regulates the formation of point contacts, which are adhesion sites that control growth cone motility. This suggests that local translation occurs at these adhesion sites that are important for axonal pathfinding, but this has not been investigated. Here, we show that RACK1 is required for BDNF-induced local translation of β-actin mRNA in growth cones. Furthermore, the ribosomal binding function of RACK1 regulates point contact formation, and axon growth and guidance. We also find that local translation of β-actin occurs at point contacts.Taken together, we show that adhesions are a targeted site of local translation within growth cones, and RACK1 is critical to the formation of point contacts and appropriate neural development.These data provide further insight into how and where local translation is regulated, and thereby leads to appropriate connectivity formation in the developing nervous system.

Local Translation Across Neural Development: A Focus on Radial Glial Cells, Axons, and Synaptogenesis

“…Furthermore, colocalization of RACK1 and β -actin mRNA with point contacts increases following BDNF stimulation ( Kershner and Welshhans, 2017 ), which results in the local translation of β -actin mRNA ( Welshhans and Bassell, 2011 ). Thus, these data suggest that local translation of β -actin mRNA may occur at adhesion sites within growth cones ( Kershner et al, 2019 ). Taken together, adhesion sites may be a direct link between extracellular stimuli and intracellular translational machinery, and thus play a crucial role in the local synthesis of β -actin mRNA to regulate axonal pathfinding during development.…”

“…Point contacts are central to axon growth and guidance in the developing nervous system (Gomez et al, 1996;. In line with this role, RACK1 knockdown in embryonic mouse cortical neurons impairs axon growth and guidance (Kershner and Welshhans, 2017;Kershner et al, 2019). Furthermore, colocalization of RACK1 and β-actin mRNA with point contacts increases following BDNF stimulation (Kershner and Welshhans, 2017), which results in the local translation of β-actin mRNA (Welshhans and Bassell, 2011).…”