Netrin-1-induced local ?-actin synthesis and growth cone guidance requires zipcode binding protein 1.

ABSTRACT: Local ?-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 ?-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 ?-actin mRNA localization was attenuated in Zbp1-deficient neurons, which impaired enrichment of ?-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 ?-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 ?-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.

SUBMITTER: Welshhans K 

PROVIDER: S-EPMC3137872 | biostudies-other | 2011 Jul

REPOSITORIES: biostudies-other