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

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.

Graphical Abstract

Highlights

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  Sex-specific synapse pruning during development is regulated by the ubiquitin pathway

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  The E3 ligase SEL-10 targets the UNC-40 netrin receptor via binding to a CPD motif

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  UNC-40 degradation leads to synapse removal only in hermaphrodites, not males

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  CPD mutations disrupt synaptic functions of UNC-40, leaving axon guidance intact

Abstract

Salzberg et al. show that local ubiquitin-mediated protein degradation in specific synapses of one sex generates sexually dimorphic circuits in C. elegans. Degradation of the netrin receptor UNC-40 in hermaphrodite synapses is necessary to establish the proper neuronal activity pattern.