Ric-8 controls Drosophila neural progenitor asymmetric division by regulating heterotrimeric G proteins

Asymmetric division of Drosophila neuroblasts (NBs) and the Caenorhabditis elegans zygote uses polarity cues provided by the Par proteins, as well as heterotrimeric G-protein-signalling that is activated by a receptor-independent mechanism mediated by GoLoco/GPR motif proteins(1,2). Another key component of this non-canonical G-protein activation mechanism is a non-receptor guanine nucleotide-exchange factor (GEF) for G alpha, RIC-8, which has recently been characterized in C. elegans and in mammals(3-6). We show here that the Drosophila Ric-8 homologue is required for asymmetric division of both NBs and pI cells. Ric-8 is necessary for membrane targeting of G alpha i, Pins and G beta 13F, presumably by regulating multiple G alpha subunit( s). Ric-8 forms an in vivo complex with Gai and interacts preferentially with GDP - G alpha i, which is consistent with Ric-8 acting as a GEF for G alpha i. Comparisons of the phenotypes of G alpha i, Ric-8, G beta 13F single and Ric-8; G beta 13F double loss-of-function mutants indicate that, in NBs, Ric-8 positively regulates G alpha i activity. In addition, G beta gamma. acts to restrict G alpha i ( and GoLoco proteins) to the apical cortex, where Gai ( and Pins) can mediate asymmetric spindle geometry.