Re-evaluating the actin-dependence of spectraplakin functions during axon growth and maintenance

TY - JOUR

T1 - Re-evaluating the actin-dependence of spectraplakin functions during axon growth and maintenance

AU - Qu, Yue

AU - Alves-Silva, Juliana

AU - Gupta, Kriti

AU - Hahn, Ines

AU - Parkin, Jill

AU - Sanchez-Soriano, Natalia

AU - Prokop, Andreas

N1 - © 2022 The Authors.

PY - 2022/4/22

Y1 - 2022/4/22

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 loose microtubule bundles 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 reduced axon growth. The underlying mechanisms are best understood for Drosophila's spectraplakin Short stop (Shot) and believed to involve cytoskeletal cross-linkage: Shot's binding to microtubules and Eb1 via its C-terminus has been thoroughly investigated, whereas its F-actin interaction via N-terminal calponin homology (CH) domains is little understood. 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) similarly existing also in mammalian spectraplakins.

AB - 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 loose microtubule bundles 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 reduced axon growth. The underlying mechanisms are best understood for Drosophila's spectraplakin Short stop (Shot) and believed to involve cytoskeletal cross-linkage: Shot's binding to microtubules and Eb1 via its C-terminus has been thoroughly investigated, whereas its F-actin interaction via N-terminal calponin homology (CH) domains is little understood. 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) similarly existing also in mammalian spectraplakins.

KW - Drosophila

KW - axons

KW - microtubules

KW - actin

KW - neurodevelopment

KW - genetic tools

U2 - 10.1002/dneu.22873

DO - 10.1002/dneu.22873

M3 - Article

SN - 1932-8451

JO - Developmental Neurobiology

JF - Developmental Neurobiology

ER -