Wingless Signaling at Synapses Is Through Cleavage and Nuclear Import of Receptor DFrizzled2

Abstract

Wingless secretion provides pivotal signals during development by activating transcription of target genes. At Drosophila synapses, Wingless is secreted from presynaptic terminals and is required for synaptic growth and differentiation. Wingless binds the seven-pass transmembrane DFrizzled2 receptor, but the ensuing events at synapses are not known. We show that DFrizzled2 is endocytosed from the postsynaptic membrane and transported to the nucleus. The C terminus of DFrizzled2 is cleaved and translocated into the nucleus; the N-terminal region remains just outside the nucleus. Translocation of DFrizzled2-C into the nucleus, but not its cleavage and transport, depends on Wingless signaling. We conclude that, at synapses, Wingless signal transduction occurs through the nuclear localization of DFrizzled2-C for potential transcriptional regulation of synapse development.

Plasticity and Second Messengers During Synapse Development

“…These observations suggest that Wg has an essential function in the development of the most basic structures required for synaptic function, and that it might be one of the initial signals for new synapse formation. Similar morphological abnormalities are elicited by hypomorphic dfz2 alleles (Mathew et al, 2005). In addition, the serine/threonine kinase Gsk3-ß/Shaggy is enriched at presynaptic boutons (Packard et al, 2002), and defects similar to those observed in wg and dfz2 mutants are observed in shaggy mutants (Franco et al, 2004).…”

Wnts: up-and-coming at the synapse

“…The effect of a Wnt member on postsynaptic morphogenesis raises the possibility that Wnt signaling might not only function in a retrograde fashion during synapse development, but that it might also operate as an anterograde, or even an autocrine, signal. This view is supported by studies in Drosophila, in which an anterograde signaling function at the neuromuscular junction (NMJ) has been demonstrated [20]. Thus, in the mammalian CNS, Wnts seem to function in a retrograde manner to regulate the differentiation of the presynaptic compartment, and they activate either a divergent canonical pathway or the PCP pathway (Box 1).…”

“…Nevertheless, DFz2 trafficking to the nucleus required endocytosis and back-transport of vesicles, as evidenced by the analysis of transgenic flies that interfered with these functions, and by examining the in vivo trafficking of endogenous DFz2 from the NMJ to the muscle nucleus [20]. The importance of this pathway was demonstrated by rescue experiments: whereas a full-length dfz2 transgene expressed in muscles rescued the dfz2 mutant defects in bouton number, a transgene lacking the cleavage site did not.…”

“…The importance of this pathway was demonstrated by rescue experiments: whereas a full-length dfz2 transgene expressed in muscles rescued the dfz2 mutant defects in bouton number, a transgene lacking the cleavage site did not. Notably, expressing the DFz2C fragment did not bypass the requirement for Wg signaling, raising the possibility that DFz2C is modified in a Wg-dependent fashion before import [20].…”

“…The search for the transduction cascade activated by Wg at the Drosophila NMJ led to the finding of a previously unrecognized alternative Wnt pathway, the Fz nuclear import pathway (FNI) [20] (Figure 1c and Box 2). Using antibodies recognizing the extracellular Nand intracellular C-terminus of DFz2 (DFz2N and DFz2C), it was found that, although both antibodies labeled the NMJ, the DFz2C antibody also labeled punctate structures within muscle nuclei, and DFz2N immunoreactivity was observed at the nuclear periphery.…”