GEFs and Rac GTPases control directional specificity of neurite extension along the anterior-posterior axis

Although previous studies have identified many extracellular guidance molecules and intracellular signaling proteins that regulate axonal outgrowth and extension, most were conducted in the context of unidirectional neurite growth, in which the guidance cues either attract or repel growth cones. Very few studies addressed how intracellular signaling molecules differentially specify bidirectional outgrowth. Here, using the bipolar PLM neurons in C. elegans, we show that the guanine nucleotide exchange factors (GEFs) UNC-73/Trio and TIAM-1 promote anterior and posterior neurite extension, respectively. The Rac subfamily GTPases act downstream of the GEFs; CED-10/Rac1 is activated by TIAM-1, whereas CED-10 and MIG-2/RhoG act redundantly downstream of UNC-73. Moreover, these two pathways antagonize each other and, thus, regulate the directional bias of neuritogenesis. Our study suggests that directional specificity of neurite extension is conferred through the intracellular activation of distinct GEFs and Rac GTPases.\n\nSignificance StatementMost previous studies on intracellular signaling during neurite guidance were performed in the context of unidirectional neurite growth. They could not address the molecular basis of directional outgrowth of multiple neurites mainly because of the lack of a good model system. Using a pair of bipolar neurons in the nematode Caenorhabditis elegans, we found that distinct sets of intracellular molecules are required for neurite extension towards the anterior and the posterior. Moreover, signaling pathways that promote neurite extension in different directions antagonize each other to achieve balanced growth. Therefore, our study offers an in vivo example for a long-standing concept that spatially selective activation of intracellular signaling molecules could enable a diverse range of neuronal growth patterns.