Abstract

Axons are the enormously long, cable-like neuronal extensions that wire our nervous system. The formation and prolonged maintenance of these delicate structures for an organism’s lifetime, requires parallel bundles of microtubules (MTs), which form the structural backbones and highways for life-sustaining transport in axons. In ageing we lose 50% of our axons, and far more in neurodegeneration; under these conditions, axonal MTs often lose their bundled appearances forming areas of disorganisation. To understand this deteriorating condition, we use Drosophila and study the various mechanisms that promote axonal MT bundle organisation during development and maintenance.

From our work, we developed the model of “local axon homeostasis”. It proposes that the axon is a high-force environment favouring MT disorganisation by default and, hence, requiring regulatory mechanisms that actively tame MTs into bundles (Voelzmann et al., 2016, Brain Res Bulletin 126, 226ff.). Three such ‘MT taming’ mechanisms will be presented: (A) Bundle formation and maintenance requires continued MT polymerisation, and we have achieved unprecedented understanding of the machinery driving this process. (B) A key mechanism downstream of MT polymerisation is the guidance of polymerising MTs in parallel to the axonal surface into parallel bundles, which depends on actin, spectraplakins and Eb1. (C) Finally, Efa6 acts as MT-eliminating factor at the axonal cortex serving as a quality control mechanism by taking out disorganised MTs.

By studying the different classes of MT regulators within the functional networks or machinery orchestrating axonal MT bundles, we gain important new understanding of fundamental axonal cell biology – required to understand the processes of the formation, plastic maintenance, regeneration and age-or disease-related decay of axons.