cGMP-Dependent Protein Kinase Encoded by foraging Regulates Motor Axon Guidance in Drosophila by Suppressing Lola Function

Correct pathfinding and target recognition of a developing axon are exquisitely regulated processes that require multiple guidance factors. Among these factors, the second messengers, cAMP and cGMP, are known to be involved in establishing the guidance cues for axon growth through different intracellular signaling pathways. However, whether and how cGMP-dependent protein kinase (PKG) regulates axon guidance remains poorly understood. Here, we show that the motor axons of intersegmental nerve b (ISNb) in the Drosophila embryo display targeting defects during axon development in the absence of foraging (for), a gene encoding PKG. In vivo tag expression revealed PKG to be present in the ventral nerve code at late embryonic stages, supporting its function in embryonic axon guidance. Mechanistic studies showed that the transcription factor longitudinal lacking (lola) genetically interacts with for. PKG physically associates with the LolaT isoform via the C-terminal zinc-finger-containing domain. Overexpression of PKG leads to the cytoplasmic retention of LolaT in S2 cells, suggesting a role for PKG in mediating the nucleocytoplasmic trafficking of Lola. Together, these findings reveal a novel function of PKG in regulating the establishment of neuronal connectivity by sequestering Lola in the cytoplasm.