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. Here we use Drosophila wrapping glia, which ensheathe peripheral axons to study the function and development of non-myelinating ensheathment. We developed a new SplitGal4 intersectional driver to target wrapping glia for genetic ablation and found that loss of wrapping glia severely impaired larval locomotor behavior. We performed an in vivo RNAi screen in Drosophila to identify glial genes required for axon ensheathment during development and identified the conserved receptor tyrosine kinase Discoidin domain receptor (Ddr). In larval peripheral nerves, loss of Ddr resulted in severely reduced 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, despite severe impairment of ensheathment, the residual wrapping in Ddr mutants was sufficient to support basic circuit function during larval stages. In adult nerves, loss of Ddr from glia decreased long-term survival of sensory neurons and significantly reduced axon caliber in an identifiable neuron 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 and nerve growth.