Dataset Information

The microtubule regulator ringer functions downstream from the RNA repair/splicing pathway to promote axon regeneration.

ABSTRACT: Promoting axon regeneration in the central and peripheral nervous system is of clinical importance in neural injury and neurodegenerative diseases. Both pro- and antiregeneration factors are being identified. We previously reported that the Rtca mediated RNA repair/splicing pathway restricts axon regeneration by inhibiting the nonconventional splicing of Xbp1 mRNA under cellular stress. However, the downstream effectors remain unknown. Here, through transcriptome profiling, we show that the tubulin polymerization-promoting protein (TPPP) ringmaker/ringer is dramatically increased in Rtca-deficient Drosophila sensory neurons, which is dependent on Xbp1. Ringer is expressed in sensory neurons before and after injury, and is cell-autonomously required for axon regeneration. While loss of ringer abolishes the regeneration enhancement in Rtca mutants, its overexpression is sufficient to promote regeneration both in the peripheral and central nervous system. Ringer maintains microtubule stability/dynamics with the microtubule-associated protein futsch/MAP1B, which is also required for axon regeneration. Furthermore, ringer lies downstream from and is negatively regulated by the microtubule-associated deacetylase HDAC6, which functions as a regeneration inhibitor. Taken together, our findings suggest that ringer acts as a hub for microtubule regulators that relays cellular status information, such as cellular stress, to the integrity of microtubules in order to instruct neuroregeneration.

SUBMITTER: Vargas EJM

PROVIDER: S-EPMC7000917 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The microtubule regulator <i>ringer</i> functions downstream from the RNA repair/splicing pathway to promote axon regeneration.

Vargas Ernest J Monahan EJM Matamoros Andrew J AJ Qiu Jingyun J Jan Calvin H CH Wang Qin Q Gorczyca David D Han Tina W TW Weissman Jonathan S JS Jan Yuh Nung YN Banerjee Swati S Song Yuanquan Y

Genes & development 20200109 3-4

Promoting axon regeneration in the central and peripheral nervous system is of clinical importance in neural injury and neurodegenerative diseases. Both pro- and antiregeneration factors are being identified. We previously reported that the Rtca mediated RNA repair/splicing pathway restricts axon regeneration by inhibiting the nonconventional splicing of <i>Xbp1</i> mRNA under cellular stress. However, the downstream effectors remain unknown. Here, through transcriptome profiling, we show that t ...[more]

PMID: 31919191

Similar Datasets

Project description:UnlabelledDelivery of proteins and organelles to the growth cone during axon extension relies on anterograde transport by kinesin motors. Though critical for neural circuit development, the mechanisms of cargo-specific anterograde transport during axon extension are only starting to be explored. Cargos of particular importance for axon outgrowth are microtubule modifiers, such as SCG10 (Stathmin-2). SCG10 is expressed solely during axon extension, localized to growth cones, and essential for axon outgrowth; however, the mechanisms of SCG10 transport and activity were still debated. Using zebrafish mutants and in vivo imaging, we identified the Kif1B motor and its interactor Kif1 binding protein (KBP) as critical for SCG10 transport to axon growth cones and complete axon extension. Axon truncation in kbp(st23) mutants can be suppressed by SCG10 overexpression, confirming the direct relationship between decreased SCG10 levels and failed axon outgrowth. Live imaging revealed that the reduced levels of SCG10 in kbp(st23) mutant growth cones led to altered microtubule stability, defining the mechanistic basis of axon truncation. Thus, our data reveal a novel role for the Kif1B-KBP complex in the anterograde transport of SCG10, which is necessary for proper microtubule dynamics and subsequent axon extension.Significance statementTogether, our data define the mechanistic underpinnings of failed axon outgrowth with loss of KBP or its associated motor, Kif1B. In addition, we provide conclusive evidence that this defect results from disruption of anterograde transport of SCG10. This is one of the first examples of a motor to be implicated in the essential transport of a discreet cargo necessary for axon extension. In addition, counter to previous in vitro and cell culture results, neither loss of the Kif1B motor nor KBP resulted in inhibition of mitochondrial transport. Altogether, our work links transport of SCG10 to the regulation of microtubule dynamics in the axon growth cone and enhances our understanding of this process during axon outgrowth.

Dataset Information

The microtubule regulator ringer functions downstream from the RNA repair/splicing pathway to promote axon regeneration.

Publications

The microtubule regulator <i>ringer</i> functions downstream from the RNA repair/splicing pathway to promote axon regeneration.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets