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Genes Dev. 2020 Feb 1;34(3-4):194-208. doi: 10.1101/gad.331330.119. Epub 2020 Jan 9.

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

Vargas EJM#1,2, Matamoros AJ#1,3, Qiu J#1,3, Jan CH4,5, Wang Q1,3, Gorczyca D5,6,7, Han TW5,6,7, Weissman JS4,5, Jan YN5,6,7, Banerjee S8, Song Y1,3.

Author information

1
Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
2
Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
3
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
4
Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, California 94158, USA.
5
Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California 94158, USA.
6
Department of Physiology, University of California at San Francisco, San Francisco, California 94158, USA.
7
Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94158, USA.
8
Department of Cellular and Integrative Physiology, Long School of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229, USA.
#
Contributed equally

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.

KEYWORDS:

Drosophila; HDAC6; MAP1B; Rtca; TPPP; axon regeneration; dendritic arborization neuron; futsch; microtubule; ringer

PMID:
31919191
PMCID:
PMC7000917
[Available on 2020-08-01]
DOI:
10.1101/gad.331330.119
[Indexed for MEDLINE]

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