Control of Wnt Trans-Synaptic Signaling by Secreted Extracellular Regulators

Abstract

In the nervous system, Wnts act as potent regulators of synaptic connectivity, architecture, neurotransmission strength and activity-dependent plasticity. As the founding Wnt, Drosophila Wingless (Wg) has key roles at the glutamatergic neuromuscular junction (NMJ) synapse. Wg is secreted from both 1) neuronal presynaptic boutons and 2) glia to bind pre- and postsynaptic Frizzled-2 (Fz2) receptors and activate downstream signal transduction modulating synapse structure and function. Notum is a secreted carboxylesterase that cleaves a lipid from Wg, rendering if less able to binds Fz2, and therefore reduces Wg signaling. Cow is a secreted heparan sulfate proteoglycan that binds Wg to carry it away from the source and therefore also reduces Wg signaling. Most synaptic phenotypes of notum and cow mutants mimic Wg overexpression including overabundance of type 1b boutons/synapses and elevated neurotransmission. Correcting Wg levels by removal of a copy of wg suppresses notum null phenotypes. A nonallelic complementation genetic test supports that Cow and Notum both work through Wg to regulate bouton number. Tethering Wg to the membrane suppresses the cow null phenotype, suggesting that Wg must be diffusible for Cow to act on it. Overall, this body of work characterizes two Drosophila Wg-binding extracellular regulators with mammalian homologs; Notum and Carrier of Wingless (Cow), with previously unknown neuronal functions.