The Microtubule Regulatory Protein Stathmin Is Required to Maintain the Integrity of Axonal Microtubules in <i>Drosophila</i>

<div><p>Axonal transport, a form of long-distance, bi-directional intracellular transport that occurs between the cell body and synaptic terminal, is critical in maintaining the function and viability of neurons. We have identified a requirement for the stathmin (<i>stai</i>) gene in the maintenance of axonal microtubules and regulation of axonal transport in <i>Drosophila</i>. The <i>stai</i> gene encodes a cytosolic phosphoprotein that regulates microtubule dynamics by partitioning tubulin dimers between pools of soluble tubulin and polymerized microtubules, and by directly binding to microtubules and promoting depolymerization. Analysis of <i>stai</i> function in <i>Drosophila</i>, which has a single <i>stai</i> gene, circumvents potential complications with studies performed in vertebrate systems in which mutant phenotypes may be compensated by genetic redundancy of other members of the <i>stai</i> gene family. This has allowed us to identify an essential function for <i>stai</i> in the maintenance of the integrity of axonal microtubules. In addition to the severe disruption in the abundance and architecture of microtubules in the axons of <i>stai</i> mutant <i>Drosophila</i>, we also observe additional neurological phenotypes associated with loss of <i>stai</i> function including a posterior paralysis and tail-flip phenotype in third instar larvae, aberrant accumulation of transported membranous organelles in <i>stai</i> deficient axons, a progressive bang-sensitive response to mechanical stimulation reminiscent of the class of <i>Drosophila</i> mutants used to model human epileptic seizures, and a reduced adult lifespan. Reductions in the levels of Kinesin-1, the primary anterograde motor in axonal transport, enhance these phenotypes. Collectively, our results indicate that <i>stai</i> has an important role in neuronal function, likely through the maintenance of microtubule integrity in the axons of nerves of the peripheral nervous system necessary to support and sustain long-distance axonal transport.</p>