TY - JOUR T1 - Re-evaluating the actin-dependence of spectraplakin functions during axon growth and maintenance JF - bioRxiv DO - 10.1101/2021.11.21.469398 SP - 2021.11.21.469398 AU - Yue Qu AU - Juliana Alves-Silva AU - Kriti Gupta AU - Ines Hahn AU - Jill Parkin AU - Natalia Sánchez-Soriano AU - Andreas Prokop Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/11/21/2021.11.21.469398.abstract N2 - Axons are the long and slender processes of neurons constituting the biological cables that wire the nervous system. The growth and maintenance of axons require bundles of microtubules that extend through their entire length. Understanding microtubule regulation is therefore an essential aspect of axon biology. Key regulators of neuronal microtubules are the spectraplakins, a well-conserved family of cytoskeletal cross-linkers that underlie neuropathies in mouse and humans. Spectraplakin deficiency in mouse or Drosophila causes severe decay of microtubule bundles and axon growth inhibition. The underlying mechanisms are best understood for Drosophila Short stop (Shot) and believed to involve cytoskeletal cross-linkage: the N-terminal calponin homology (CH) domains bind to F-actin, and the C-terminus to microtubules and Eb1. Here we have gained new understanding by showing that the F-actin interaction must be finely balanced: altering the properties of F-actin networks or deleting/exchanging Shot’s CH domains induces changes in Shot function - with a Lifeact-containing Shot variant causing remarkable remodelling of neuronal microtubules. In addition to actin-MT cross-linkage, we find strong indications that Shot executes redundant MT bundle-promoting roles that are F-actin-independent. We argue that these likely involve the neuronal Shot-PH isoform, which is characterised by a large, unexplored central plakin repeat region (PRR). Work on PRRs might therefore pave the way towards important new mechanisms of axon biology and architecture that might similarly apply to central PRRs in mammalian spectraplakins.Competing Interest StatementThe authors have declared no competing interest. ER -