Wnt Secretion Is Regulated by the Tetraspan Protein HIC-1 through Its Interaction with Neurabin/NAB-1

The aberrant regulation of Wnt secretion is implicated in various neurological diseases. However, the mechanisms of Wnt release are still largely unknown. Here we describe the role of a C. elegans tetraspan protein, HIC-1, in maintaining normal Wnt release. We show that HIC-1 is expressed in cholinergic synapses and that mutants in hic-1 show increased levels of the acetylcholine receptor AChR/ACR-16. Our results suggest that HIC-1 maintains normal AChR/ACR-16 levels by regulating normal Wnt release from presynaptic neurons, as hic-1 mutants show an increase in secreted Wnt from cholinergic neurons. We further show that HIC-1 affects Wnt secretion by modulating the actin cytoskeleton through its interaction with the actin-binding protein NAB-1. In summary, we describe a protein, HIC-1, that functions as a neuromodulator by affecting postsynaptic AChR/ACR-16 levels by regulating presynaptic Wnt release from cholinergic motor neurons.