Laminin and BDNF synergistically induce local translation in axonal growth cones

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 Laminin and BDNF synergistically induce local translation in axonal growth cones

Nikita Kirkise1 and Kristy Welshhans1,2* 

1 Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA; 2 Carolina Autism and Neurodevelopment (CAN) Research Center, University of South Carolina, Columbia, SC 29208, USA 

 *Corresponding author: kwelshhans@sc.edu 

 Running title: Laminin regulates local translation

ABSTRACT The laminins are a family of extracellular matrix proteins that regulate numerous cellular processes, including adhesion, neurite outgrowth, and axon guidance. However, it remains unclear whether laminin regulates axon guidance through local translation. Here, we show that laminin is necessary for local translation in axonal growth cones. Local translation is significantly increased in growth cones of embryonic day 17 mouse cortical neurons, either cultured on or acutely stimulated with soluble laminin 111, in the presence of BDNF. When cultured on laminin isoforms 211 or 221 in the presence of BDNF, there was a remarkable decrease in local translation in growth cones. Using a puromycin-proximity ligation assay to examine newly synthesized b-actin specifically, we find a significant increase in growth cones of neurons cultured on laminin 111 in the presence of BDNF. However, soluble laminin 111 alone results in a significant reduction in nascent b-actin protein synthesis. These results indicate that laminin isoforms can act in multiple ways, including synergistically with guidance cues and independently, to modulate local mRNA translation, thereby differentially influencing axon growth and guidance during development. 

 SUMMARY STATEMENT Local translation in axons is critical for axon guidance. Laminin, a key component of the extracellular matrix, is necessary to induce local translation and thus mediate axon growth and guidance. 

 INTRODUCTION Accurate neural wiring is important for the formation of a healthy, functional brain. Changes in neural wiring or the failure to connect with synaptic targets can give rise to various neurological disorders (Van Battum et al., 2015). During development, this neural network is formed through axon guidance, wherein neuronal processes are directed to and establish connections with their synaptic targets (Bellon and Mann, 2018). Axon guidance is mediated by growth cones, which are highly dynamic and motile motor and sensory structures located at the tips of pathfinding axons. Growth cones respond to extracellular cues in their environment, which can be attractive or repulsive, as well as diffusible or contact-mediated (Gomez et al., 1996, Lowery and Vactor, 2009, Bixby and Harris, 1991, McFarlane and Holt, 1997). These cues are sensed by the receptors present on growth cone filopodia and lamellipodia, initiating signaling mechanisms that reorganize the cytoskeleton and allow the growth cone to advance towards, stall, or turn away from the cue (Myers et al., 2011). Contact-mediated cues, such as extracellular matrix (ECM) proteins, are critical in axon guidance. Laminin is a major component of the ECM and is widely expressed in both the peripheral and central nervous systems (Barros et al., 2011, McKerracher et al., 1996, Myers et al., 2011). Numerous studies have reported that laminin regulates axon guidance (Barros et al., 2011, Kuhn et al., 1995, McKerracher et al., 1996, Bonner and O'Connor, 2001, Paulus and Halloran, 2006). Moreover, netrin-1 is an attractive guidance cue for retinal neurons, but when a high concentration of laminin substrate is also present, netrin-1 becomes repellent to these neurons (Hopker et al., 1999). Similarly, retinal ganglion cells collapse in the presence of EphB and laminin, but when L1 is also present, then growth cone pausing occurs (Suh et al., 2004). Thus, laminin acts in concert with other guidance molecules to differentially remodel the cytoskeleton, but we currently have limited knowledge about how this signaling from multiple cues is integrated.

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