Abstract
Increasing evidence indicates that guidance molecules used during development for cellular and axonal navigation also play roles in synapse maturation and homeostasis. In C. elegans the netrin receptor UNC-40/DCC controls the growth of dendritic-like muscle cell extensions towards motoneurons and is required to recruit type A GABA receptors (GABAARs) at inhibitory neuromuscular junctions. Here we show that activation of UNC-40 assembles an intracellular synaptic scaffold by physically interacting with FRM-3, a FERM protein orthologous to FARP1/2. FRM-3 then recruits LIN-2, the ortholog of CASK, that binds the synaptic adhesion molecule NLG-1/Neuroligin and physically connects GABAARs to prepositioned NLG-1 clusters. These processes are orchestrated by the synaptic organizer CePunctin/MADD-4, which controls the localization of GABAARs by positioning NLG-1/neuroligin at synapses and regulates the synaptic content of GABAARs through the UNC-40-dependent intracellular scaffold. Since DCC is detected at GABA synapses in mammals, DCC might also tune inhibitory neurotransmission in the mammalian brain.
Highlights
Increasing evidence indicates that guidance molecules used during development for cellular and axonal navigation play roles in synapse maturation and homeostasis
We identify here two proteins, FRM-3 and LIN-2, that implement the function of UNC-40 for the recruitment of GABAARs at inhibitory neuromuscular junctions (NMJs)
We show that UNC-40 recruits FRM-3, a FERM (p4.1, Ezrin, Radixin, Moesin) protein orthologous to FARP1/2, by a physical interaction between the intracellular P3 domain of UNC-40 and the FERMFA tandem of FRM-3
Summary
Increasing evidence indicates that guidance molecules used during development for cellular and axonal navigation play roles in synapse maturation and homeostasis. FRM-3 recruits LIN-2, the ortholog of CASK, that binds the synaptic adhesion molecule NLG-1/Neuroligin and physically connects GABAARs to prepositioned NLG-1 clusters These processes are orchestrated by the synaptic organizer CePunctin/ MADD-4, which controls the localization of GABAARs by positioning NLG-1/neuroligin at synapses and regulates the synaptic content of GABAARs through the UNC-40-dependent intracellular scaffold. In the presence of UNC5, netrin would trigger the formation of DCC/ UNC5 heterodimers that mediate repulsive behaviors[12] This long-range chemotatic gradient model has recently been revisited after analysis of axonal growth in mice where netrin expression was inactivated in specific subregions of the developing nervous system[13,14,15].
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