The Tripartite Motif Protein MADD-2 Functions with the Receptor UNC-40 (DCC) in Netrin-Mediated Axon Attraction and Branching

SummaryNeurons innervate multiple targets by sprouting axon branches from a primary axon shaft. We show here that the ventral guidance factor unc-6 (Netrin), its receptor unc-40 (DCC), and the gene madd-2 stimulate ventral axon branching in C. elegans chemosensory and mechanosensory neurons. madd-2 also promotes attractive axon guidance to UNC-6 and assists unc-6- and unc-40-dependent ventral recruitment of the actin regulator MIG-10 in nascent axons. MADD-2 is a tripartite motif protein related to MID-1, the causative gene for the human developmental disorder Opitz syndrome. MADD-2 and UNC-40 proteins preferentially localize to a ventral axon branch that requires their function; genetic results indicate that MADD-2 potentiates UNC-40 activity. Our results identify MADD-2 as an UNC-40 cofactor in axon attraction and branching, paralleling the role of UNC-5 in repulsion, and provide evidence that targeting of a guidance factor to specific axonal branches can confer differential responsiveness to guidance cues.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (178 K)Download as PowerPoint slideHighlights► UNC-6 (Netrin), its receptor UNC-40 (DCC), and the TRIM protein MADD-2 promote axon branching ► MADD-2 and UNC-40 proteins are localized to the affected axon branch ► MADD-2 stimulates axon attraction to Netrin by acting as an UNC-40 cofactor ► MADD-2 enables UNC-40 to recruit MIG-10, an actin-binding effector protein