The difference among the Or47b, the Or46a, and the Or22a neurons in rich and Rab6 mutants may reflect this difference. Here, we report the identification of mutations in rich, a gene that is evolutionarily

conserved from worms to human. rich is required for synaptic specificity in Drosophila eyes and olfactory receptor neurons and acts together with Rab6. Our data define a role for Rich and Rab6 in regulating axon targeting in the eye by regulating CadN trafficking in a subset of neurons to control target specificity. Rab6 has been implicated in multiple membrane trafficking pathway and numerous “downstream” effectors have been identified (Valente et al., 2010). However, the “upstream” regulators have not yet been identified in higher eukaryotes. The Ric1p forms Tenofovir clinical trial a complex with Rgp1p in yeast and promotes GTP exchange for the yeast Rab6 homolog Ypt6 (Siniossoglou et al., 2000). Surprisingly, although Rab6 family proteins check details are highly conserved (similarity between

Rab6 and Ypt6 is 84%), the Ric1p and Rgp1p only exhibit limited similarity with the fly and vertebrate homologs (Figure 3B). In addition, fly Rich contains several WD40 domains not found in the yeast protein, yet both the RIC1 and WD40 domains bind to Rab6. Importantly, rich and Rab6 show obvious genetic interactions and similarities in phenotypes in flies. However, we were not able to detect GTP exchange activity of Rich, nor were we able to find an interaction between Rich and the Drosophila Rgp1p like protein. Therefore, it is likely that Rich is using other interactors to regulate Rab6 activity. Moreover, we found that Rich/Rab6 regulates CadN trafficking in a cell type specific manner, yet both Rab6 and Rich are broadly expressed in brains. Hence, the other Rich interactors might be key to modulate Rab6 activity differentially in various cell types. In the medulla, several all cell surface proteins have been identified that regulate R7 or R8 targeting in a cell-type-specific manner. For example, CadN (Lee et al., 2001), as well as DLAR (Clandinin et al., 2001) and PTP69D

(Newsome et al., 2000), mainly regulate R7 but not R8 synaptic specificity. On the other hand, Jeb (Bazigou et al., 2007), together with Flamingo (fmi) (Senti et al., 2003) and Golden goal (gogo) (Tomasi et al., 2008) direct R8 but not R7 targeting. The expression patterns of these cell surface molecules are broad, whereas their cell type specific functions are quite defined. It is therefore likely that these proteins depend on a regulated set of trafficking rules to achieve synaptic specificity. However, so far, only Sec15 has been shown to affect synaptic specificity, and in sec15 mutants, the synaptic specificity of both R7 and R8 are affected ( Mehta et al., 2005). Here, we established a role for two proteins that have not yet been implicated in trafficking of important cell surface proteins in the CNS like CadN.