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Elife. 2018 Aug 7;7. pii: e34593. doi: 10.7554/eLife.34593.

Gradient-reading and mechano-effector machinery for netrin-1-induced axon guidance.

Author information

1
Division of Biological Science, Nara Institute of Science and Technology, Ikoma, Japan.
2
Department of Neurobiology, Physiology and Behavior, University of California, Davis, Davis, United States.
3
Department of Applied Chemistry, Graduate School of Engineering, University of Tokyo, Tokyo, Japan.
#
Contributed equally

Abstract

Growth cones navigate axonal projection in response to guidance cues. However, it is unclear how they can decide the migratory direction by transducing the local spatial cues into protrusive forces. Here we show that knockout mice of Shootin1 display abnormal projection of the forebrain commissural axons, a phenotype similar to that of the axon guidance molecule netrin-1. Shallow gradients of netrin-1 elicited highly polarized Pak1-mediated phosphorylation of shootin1 within growth cones. We demonstrate that netrin-1-elicited shootin1 phosphorylation increases shootin1 interaction with the cell adhesion molecule L1-CAM; this, in turn, promotes F-actin-adhesion coupling and concomitant generation of forces for growth cone migration. Moreover, the spatially regulated shootin1 phosphorylation within growth cones is required for axon turning induced by netrin-1 gradients. Our study defines a mechano-effector for netrin-1 signaling and demonstrates that shootin1 phosphorylation is a critical readout for netrin-1 gradients that results in a directional mechanoresponse for axon guidance.

KEYWORDS:

axon guidance; cell biology; chemotaxis; clutch; gradient sensing; growth cone; mouse; neuroscience; rat; shootin1

PMID:
30082022
PMCID:
PMC6080949
DOI:
10.7554/eLife.34593
[Indexed for MEDLINE]
Free PMC Article

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