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.

Microtubule-associated protein 1B is implicated in stem cell commitment and nervous system regeneration in planarians

“…It has been proposed that they act as scaffold proteins between cytoskeleton and membranes, probably by functionally linking different proteins [ 41 ]. The Drosophila MAP1B homolog, Futsch , has an important role in stabilizing the active zone where it regulates the release of neurotransmitters [ 42 , 43 ], and in neuronal retention in adult flies [ 44 ]; Futsch mutants have impaired axon regeneration [ 45 ]. So it is possible to hypothesize that also DjMap1B , like the other members of MAP1B family, is involved in neuroarchitecture maintenance and neurosecretion throughout an action at the level of the cytoskeleton filaments present in the nerve cell terminal.…”

Truncated TPPP – An Endopterygota-specific protein

“…This function is conserved in animals [ 4 ], including TPPP of D. melanogaster , CG45057. The fruit fly protein regulates microtubule stabilization and axonal extension during embryonic development [ 5 ], as well as synaptic microtubule organization via the acetylation level of the microtubule network [ 16 ]; and acts probably as a hub for microtubule regulators [ 17 ].…”

Molecular mechanisms of neurite regeneration and repair: insights from C. elegans and Drosophila

“…Generally, the Drosophila da neuron can be classified into four classes (class I-IV) based on the complexity of their dendrite pattern and can be further divided into several subgroups according to their location (e.g., dorsal, ventral). Noticeably, the regeneration after neurite injury exhibits different abilities and mechanisms among subgroups and between the central and peripheral nervous systems (CNS and PNS) (Rao and Rolls 2017 ; Vargas et al 2020 ). These distinctions can specifically give inspiration for our understanding of the more complex nerve system in humans.…”