A tug of war between DCC and ROBO1 signaling during commissural axon guidance

Dailey-Krempel, Brianna; Martin, Andrew L.; Jo, Ha-neul; Junge, Harald J.; Chen, Zhe

doi:10.1016/j.celrep.2023.112455

Cited by 2 publications

(1 citation statement)

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“…Ntn1 deletion is associated with several axon guidance defects including agenesis of the corpus callosum, absence of hippocampal and spinal commissures, and disorganized thalamocortical projections (Mitchell et al, 1996;Braisted et al, 2000;Bradford et al, 2009;Bin et al, 2015). Interestingly, netrin-1 induces both attractive and repulsive responses in vivo (Keino-Masu et al, 1996;Srivatsa et al, 2014;Dailey-Krempel et al, 2023), but the mechanisms mediating these diverse responses are not fully understood (Boyer and Gupton, 2018). Modeling results in vivo, we previously found that a gradient of chicken netrin-1 induced biphasic axon turning responses in vitro, which was dependent upon the local concentration of netrin-1, with attractive axon turning occurring at lower concentrations of a netrin gradient and repulsive axon turning occurring at higher concentrations (Taylor et al, 2015;Boyer et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

TRIM9 controls growth cone responses to netrin through DCC and UNC5C

Mutalik,

O’Shaughnessy,

et al. 2024

Preprint

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The guidance cue netrin-1 promotes both growth cone attraction and growth cone repulsion. How netrin-1 elicits these diverse axonal responses, beyond engaging the attractive receptor DCC and repulsive receptors of the UNC5 family, remains elusive. Here we demonstrate that murine netrin-1 induces biphasic axonal responses in cortical neurons: attraction at lower concentrations and repulsion at higher concentrations using both a microfluidic-based netrin-1 gradient and bath application of netrin-1. TRIM9 is a brain-enriched E3 ubiquitin ligase previously shown to bind and cluster the attractive receptor DCC at the plasma membrane and regulate netrin-dependent attractive responses. However, whether TRIM9 also regulated repulsive responses to netrin-1 remained to be seen. In this study, we show that TRIM9 localizes and interacts with both the attractive netrin receptor DCC and the repulsive netrin receptor, UNC5C, and that deletion of murine Trim9 alters both attractive and repulsive responses to murine netrin-1. TRIM9 was required for netrin-1-dependent changes in surface levels of DCC and total levels of UNC5C in the growth cone during morphogenesis. We demonstrate that DCC at the membrane regulates growth cone area and show that TRIM9 negatively regulates FAK activity in the absence of netrin-1. We investigate membrane dynamics of the UNC5C receptor using pH-mScarlet fused to the extracellular domain of UNC5C. Minutes after netrin addition, levels of UNC5C at the plasma membrane drop in a TRIM9-independent fashion, however TRIM9 regulated the mobility of UNC5C in the plasma membrane in the absence of netrin-1. Together this work demonstrates that TRIM9 interacts with and regulates both DCC and UNC5C during attractive and repulsive axonal responses to netrin-1.

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