Synaptic Protein Degradation Controls Sexually Dimorphic Circuits through Regulation of DCC/UNC-40

Abstract

Summary Sexually dimorphic circuits underlie behavioral differences between the sexes, yet the molecular mechanisms involved in their formation are poorly understood. We show here that sexually dimorphic connectivity patterns arise in C. elegans through local ubiquitin-mediated protein degradation in selected synapses of one sex but not the other. Specifically, synaptic degradation occurs via binding of the evolutionary conserved E3 ligase SEL-10/FBW7 to a phosphodegron binding site of the netrin receptor UNC-40/DCC (Deleted in Colorectal Cancer), resulting in degradation of UNC-40. In animals carrying an undegradable unc-40 gain-of-function allele, synapses were retained in both sexes, compromising the activity of the circuit without affecting neurite guidance. Thus, by decoupling the synaptic and guidance functions of the netrin pathway, we reveal a critical role for dimorphic protein degradation in controlling neuronal connectivity and activity. Additionally, the interaction between SEL-10 and UNC-40 is necessary not only for sex-specific synapse pruning, but also for other synaptic functions. These findings provide insight into the mechanisms that generate sex-specific differences in neuronal connectivity, activity, and function.

Neurodevelopment: UNC-40/DCC and the Patterning of Neural Circuits

“…A computational approach [6] identified a potential CPD site in the cytoplasmic region of the UNC-40 receptor for the netrin UNC-6. The results of genetic epistasis analyses, gene expression studies, and ectopic expression experiments are consistent with a role for these genes in regulating PHB>AVG development [1]. Evidence also shows that the UNC-40 CPD site is important for SEL-10-mediated degradation.…”

“…UNC-6 and its UNC-5 and UNC-40 receptors have been shown to affect synapse patterning [9,10], but how different patterns form is a mystery. The current study from Salzberg et al [1] suggests that the UPS plays a role in patterning. Besides the PHB>AVG synapses, PHB also forms synapses with the AVA neuron (Figure 1A).…”

“…It is not well understood how neurons sculpt these precise, yet distinctive patterns. In a new study published in this issue of Current Biology, Salzberg et al [1] show that ubiquitin-mediated degradation of the Caenorhabditis elegans netrin receptor UNC-40 (homolog of DCC) occurs in a particular neuron in one sex, but not in the other, and that this event is required for the development of sex-specific synaptic patterns.…”

“…Salzberg et al [1] focused on the role of the ubiquitin-proteasome system (UPS), which targets proteins for degradation. Previous studies have indicated that ubiquitin-mediated protein degradation regulates synapse structure and function [5].…”

“…Also, the UPS is thought to regulate and integrate signaling networks through the combination of multiple E3 ligases, ubiquitin-binding effectors, and deubiquitylases [19]. In C. elegans, both SEL-10 and RPM-1 E3 ligases have been shown to regulate UNC-40mediated activities, albeit in different developmental contexts [1,20]. Future studies may reveal that the UPS plays an important role in spatially and temporally regulating UNC-40/DCC activity.…”