Discoidin domain receptor regulates ensheathment, survival, and caliber of peripheral axons

Invertebrate axons and small caliber axons in mammalian peripheral nerves are unmyelinated but still ensheathed by glia. How this type of ensheathment is controlled and its roles in supporting neuronal function remain unclear. We performed an in vivo RNAi screen in Drosophila to identify glial genes required for axon ensheathment and identified the conserved receptor tyrosine kinase Discoidin domain receptor (Ddr). In larval peripheral nerves, loss of Ddr resulted in incomplete ensheathment of axons. We found a strong dominant genetic interaction between Ddr and the fly type XV/XVIII collagen Multiplexin (Mp), suggesting Ddr functions a collagen receptor to drive wrapping of axons during development. Surprisingly, while ablation of glia that wrap axons severely impaired larval motor behavior, incomplete wrapping in Ddr mutants was sufficient to support basic circuit function. In adult nerves, loss of Ddr from glia decreased long-term survival of sensory neurons and significantly reduced axon caliber without overtly affecting ensheathment. Our data establish a crucial role for non-myelinating glia in peripheral nerve development and function across the lifespan, and identify Ddr as a key regulator of axon-glia interactions during ensheathment.