Control of Schwann Cell Myelination by DDR1 Receptor Tyrosine Kinase

In peripheral nervous system (PNS), immature Schwann cells differentiate into two functionally distinct types of mature Schwann cells: myelinating Schwann cells, which establish a one-to-one relationship with large-diameter axons and initiate the complex myelination program that enables the rapid saltatory conduction of nerve impulses, and non-myelinating Schwann cells, which envelop multiple small-diameter axons without forming myelin, but support axon survival and maintain microenvironment homeostasis. Here, we demonstrate that discoidin domain receptor 1 (DDR1) signaling plays a pivotal role in Schwann cell maturation and peripheral nerve myelination. Ddr1^-/- mice of both sexes exhibited fewer myelinating Schwann cells and profound hypomyelination, reduced nerve conduction velocity, and apparent motor dysfunction. Expression of myelin markers was markedly reduced in the mutants accompanied by the formation of abnormal myelin ultrastructure resembling "onion bulbs". Mechanistically, Ddr1 deficiency impaired Schwann cell myelination through the marked hyperactivation of the MAPK/ERK signaling pathway. These findings establish DDR1 as a novel regulator of Schwann cell myelination and highlight its potential as a therapeutic target for demyelinating neuropathies.