ZFIN ID: ZDB-PUB-190427-3
STIM1 is required for remodelling of the endoplasmic reticulum and microtubule cytoskeleton in steering growth cones
Pavez, M., Thompson, A.C., Arnott, H.J., Mitchell, C.B., D'Atri, I., Don, E.K., Chilton, J.K., Scott, E.K., Lin, J.Y., Young, K.M., Gasperini, R.J., Foa, L.
Date: 2019
Source: The Journal of neuroscience : the official journal of the Society for Neuroscience   39(26): 5095-5114 (Journal)
Registered Authors: Don, Emily, Scott, Ethan
Keywords: none
MeSH Terms:
  • Animals
  • Axon Guidance/physiology*
  • Calcium/metabolism
  • Cytoskeleton/genetics
  • Cytoskeleton/metabolism*
  • Endoplasmic Reticulum/metabolism*
  • Growth Cones/metabolism*
  • Microtubule-Associated Proteins/genetics
  • Microtubule-Associated Proteins/metabolism
  • Microtubules/genetics
  • Microtubules/metabolism*
  • Motor Neurons/metabolism
  • Pseudopodia/metabolism
  • Rats
  • Sensory Receptor Cells/metabolism
  • Stromal Interaction Molecule 1/genetics
  • Stromal Interaction Molecule 1/metabolism*
  • Zebrafish
PubMed: 31023836 Full text @ J. Neurosci.
The spatial and temporal regulation of calcium signalling in neuronal growth cones is essential for axon guidance. In growth cones, the endoplasmic reticulum (ER) is a significant source of calcium signals. However, it is not clear whether the ER is remodelled during motile events to localize calcium signals in steering growth cones. The expression of the ER-calcium sensor, stromal interacting molecule 1 (STIM1) is necessary for growth cone steering towards the calcium-dependent guidance cue BDNF, with STIM1 functioning to sustain calcium signals through store-operated calcium entry (SOCE). However, STIM1 is also required for growth cone steering away from sema-3a, a guidance cue that does not activate ER-calcium release, suggesting multiple functions of STIM1 within growth cones (Mitchell et al., 2012). STIM1 also interacts with microtubule plus-end binding proteins EB1/3 (Grigoriev et al., 2008b). Here, we show that STIM1 associates with EB1/3 in growth cones and that STIM1 expression is critical for microtubule recruitment and subsequent ER remodelling to the motile side of steering growth cones. Furthermore, we extend our data in vivo, demonstrating that zSTIM1 is required for axon guidance in actively navigating zebrafish motor neurons, regulating calcium signalling and filopodial formation. These data demonstrate that in response to multiple guidance cues, STIM1 couples microtubule organization and ER-derived calcium signals, thereby providing a mechanism where STIM1-mediated ER remodelling, particularly in filopodia, regulates spatiotemporal calcium signals during axon guidance.SIGNIFICANCE STATEMENTDefects in both axon guidance and endoplasmic reticulum (ER) function are implicated in a range of developmental disorders. During neuronal circuit development, the spatial localization of calcium signals controls the growth cone cytoskeleton to direct motility. We demonstrate a novel role for stromal interacting molecule 1 (STIM1) in regulating microtubule and subsequent ER remodelling in navigating growth cones. We show that STIM1, an activator of store-operated calcium entry, regulates the dynamics of microtubule-binding proteins EB1/3, coupling ER to microtubules, within filopodia, thereby steering growth cones. The STIM1-microtubule-ER interaction provides a new model for spatial localization of calcium signals in navigating growth cones in the nascent nervous system.