Journal
JOURNAL OF NEUROSCIENCE
Volume 31, Issue 27, Pages 9800-9813Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0166-11.2011
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Funding
- NINDS [F32NS064727]
- NICHD [R01HD046368]
- Viral Vector Core
- Microscopy Core of the Emory Neuroscience NINDS Core Facilities [P30NS055077]
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Local beta-actin synthesis in growth cones of developing axons plays an important role in growth cone steering; however, the mRNA binding proteins required for this process are unknown. Here we used Zbp1/Imp1(-/-) mice to test the hypothesis that zipcode binding protein 1 (ZBP1) is required for the regulation of beta-actin mRNA transport and local translation underlying growth cone guidance. To address the biological function of ZBP1, we developed a novel in vitro turning assay with primary cortical neuron balls having axons > 1 mm in length and demonstrate that growth cones of mammalian neurons exhibit protein synthesis-dependent attraction to either netrin-1 or brain-derived neurotrophic factor (BDNF). Interestingly, this attraction is lost in Zbp1-deficient neurons. Furthermore, BDNF-stimulated beta-actin mRNA localization was attenuated in Zbp1-deficient neurons, which impaired enrichment of beta-actin protein in the growth cone. Finally, using a photoconvertible translation reporter, we found that ZBP1 is necessary for netrin-1 stimulated local translation of beta-actin mRNA in axonal growth cones. Together, these results suggest that netrin-1- and BDNF-induced growth cone attraction required ZBP1-mediated local translation of beta-actin mRNA, and therefore ZBP1 regulates protein synthesis-dependent axon guidance. Thus, mRNA binding proteins regulating local translation can control spatiotemporal protein expression in response to guidance cues and directional cell motility.
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