Homer regulates calcium signalling in growth cone turning
Gasperini, RJ and Choi-Lundberg, DL and Thompson, MJW and Mitchell, CB and Foa, LC, Homer regulates calcium signalling in growth cone turning, Neural Development, 4, (1) pp. 1-19. ISSN 1749-8104 (2009) [Refereed Article]
Background: Homer proteins are post-synaptic density proteins with known functions in
receptor trafficking and calcium homeostasis. While they are key mediators of synaptic plasticity,
they are also known to function in axon guidance, albeit by mechanisms that are yet to be
elucidated. Homer proteins couple extracellular receptors – such as metabotropic glutamate
receptors and the transient receptor potential canonical family of cation channels – to intracellular
receptors such as inositol triphosphate and ryanodine receptors on intracellular calcium stores
and, therefore, are well placed to regulate calcium dynamics within the neural growth cone. Here
we used growth cones from dorsal root ganglia, a well established model in the field of axon
guidance, and a growth cone turning assay to examine Homer1 function in axon guidance.
Results: Homer1 knockdown reversed growth cone turning from attraction to repulsion in
response to the calcium-dependent guidance cues brain derived neurotrophic factor and netrin-1.
Conversely, Homer1 knockdown had no effect on repulsion to the calcium-independent guidance
cue Semaphorin-3A. This reversal of attractive turning suggested a requirement for Homer1 in a
molecular switch. Pharmacological experiments confirmed that the operational state of a calciumcalmodulin
dependent protein kinase II/calcineurin phosphatase molecular switch was dependent
on Homer1 expression. Calcium imaging of motile growth cones revealed that Homer1 is required
for guidance-cue-induced rise of cytosolic calcium and the attenuation of spontaneous cytosolic
calcium transients. Homer1 knockdown-induced calcium transients and turning were inhibited by
antagonists of store-operated channels. In addition, immunocytochemistry revealed the close
association of Homer1 with the store-operated proteins TRPC1 and STIM1 within dorsal root
ganglia growth cones.
Conclusion: These experiments provide evidence that Homer1 is an essential component of the
calcium signalling repertoire within motile growth cones, regulating guidance-cue-induced calcium
release and maintaining basal cytosolic calcium.