Normal Spastin Gene Dosage Is Specifically Required for Axon Regeneration

Abstract

Summary Axon regeneration allows neurons to repair circuits after trauma, but most of the molecular players remain to be identified. As microtubule rearrangements have been observed in injured neurons, we tested whether microtubule severing proteins might play a role in axon regeneration. We found that axon regeneration is extremely sensitive to levels of the microtubule severing protein spastin. While microtubule behavior in uninjured neurons was not perturbed in animals heterozygous for a spastin null allele, axon regeneration was severely disrupted in this background. Two types of axon regeneration, regeneration of an axon from a dendrite after proximal axotomy and regeneration of an axon from the stump after distal axotomy, were defective in Drosophila with one mutant copy of the spastin gene. Other types of axon and dendrite outgrowth, including regrowth of dendrites after pruning, were normal in heterozygotes. We conclude that regenerative axon growth is uniquely sensitive to spastin gene dosage.

Spastin, atlastin, and ER relocalization are involved in axon but not dendrite regeneration

“…In our previous study, we identified a link between spastin and axon regeneration, but we did not find any differences in injury-induced microtubule rearrangements between control and spastin-reduced neurons (Stone et al ., 2012). To try to understand the relationship between spastin and regeneration, we now use several different approaches.…”

“…Spastin function in mature neurons is less studied, although spastin continues to be expressed in adult rats (Solowska et al ., 2008), and adult spastin mutant flies have a progressive decline in motor skills over the long term (Sherwood et al ., 2004). At the cellular level, reduction in spastin has been associated with failure of mature neurons to regenerate axons in Drosophila (Stone et al ., 2012); however, how spastin promotes regeneration is not known.…”

Building the Neuronal Microtubule Cytoskeleton

“…MT severing by katanin and spastin is particularly important for the formation of axonal branches and dendritic development (Yu et al, 2008). Several studies have also uncovered an important role for MT severing in the outgrowth of motor neurons, the formation of NMJs, and axon regeneration (Mao et al, 2014;Stone et al, 2012). Consistent with the axonal defects in various model systems, spastin mutations have been directly linked to axonal pathologies in the human neurodegenerative disease called hereditary spastic paraplegia (HSP) (Fink, 2013).…”

Stathmin is enriched in the developing corticospinal tract

“…Recent studies in both Drosophila and mice have shown that microtubule destabilisation may be an essential part of the regrowth of axons after injury (Stone et al, 2012;Cho and Cavalli, 2012). Though a great deal of effort has been placed on understanding the extracellular milieu surrounding injured spinal cord axons (e.g., Nogo, and L1; Cohen et al, 1998;Stein and Tessier-Lavigne, 2001;WienckenBarger et al, 2004), the intrinsic growth potential of injured CST axons should also be assessed to determine if the intra-cellular mechanisms necessary to bring about appropriate axonal growth responses are in place for regeneration to happen (Harel and Strittmatter, 2006).…”