GRDN-1/Girdin regulates dendrite morphogenesis and cilium position in two specialized sensory neuron types in C. elegans.

Primary cilia are located at the dendritic tips of sensory neurons and house the molecular machinery necessary for detection and transduction of sensory stimuli. The mechanisms that coordinate dendrite extension with cilium position during sensory neuron development are not well understood. Here, we show that GRDN-1, the Caenorhabditis elegans ortholog of the highly conserved scaffold and signaling protein Girdin/GIV, regulates both cilium position and dendrite extension in the postembryonic AQR and PQR gas-sensing neurons. Mutations in grdn-1 disrupt dendrite outgrowth and mislocalize cilia to the soma or proximal axonal segments in AQR, and to a lesser extent, in PQR. GRDN-1 is localized to the basal body and regulates localization of HMR-1/Cadherin to the distal AQR dendrite. However, knockdown of HMR-1 and/or loss of SAX-7/LICAM, molecules previously implicated in sensory dendrite development in C. elegans, do not alter AQR dendrite morphology or cilium position. We find that GRDN-1 localization in AQR is regulated by UNC-116/Kinesin-1, and that correspondingly, unc-116 mutants exhibit severe AQR dendrite outgrowth and cilium positioning defects. In contrast, GRDN-1 and cilium localization in PQR is modulated by LIN-44/Wnt signaling. Together, these findings identify upstream regulators of GRDN-1, and describe new cell-specific roles for this multifunctional protein in sensory neuron development.

GIV/girdin binds exocyst subunit-Exo70 and regulates exocytosis of GLUT4 storage vesicles.

Insulin resistance (IR) is a metabolic disorder characterized by impaired glucose uptake in response to insulin. The current paradigm for insulin signaling centers upon the insulin receptor (InsR) and its substrate IRS1; the latter is believed to be the chief conduit for post-receptor signaling. We recently demonstrated that GIV, a Guanidine Exchange Factor (GEF) for the trimeric G protein, Gαi, is a major hierarchical conduit for the metabolic insulin response. By virtue of its ability to directly bind the InsR, IRS1 and PI3K, GIV enhances the InsR-IRS1-Akt-AS160 (RabGAP) signaling cascade and cellular glucose uptake via its GEF function. Phosphoinhibition of GIV-GEF by the fatty-acid/PKCθ pathway inhibits the cascade and impairs glucose uptake. Here we show that GIV directly and constitutively binds the exocyst complex subunit Exo-70 and also associates with GLUT4-storage vesicles (GSVs) exclusively upon insulin stimulation. Without GIV or its GEF function, membrane association of Exo-70 as well as exocytosis of GSVs in response to insulin are impaired. Thus, GIV is an essential component within the insulin signaling cascade that couples upstream signal transducers within the InsR and G-Protein signaling cascade to downstream vesicular trafficking events within the exocytic pathway. These findings suggest a role of GIV in coordinating key signaling and trafficking events of metabolic insulin response.