CDK14-dependent phosphorylation of neuronal FAM19A1 activates DIP2A signaling in oligodendrocytes to maintain myelin homeostasis in the adult brain

Myelination is essential for dynamic neuronal adaptation to environmental experience and neuronal plasticity. However, the communication between oligodendrocytes (OLs) and neurons remains poorly understood. Family with sequence similarity 19 member 1 (FAM19A1, TAFA1) is a neuronal chemokine-like secretory protein containing conserved cysteine residues. Here, we show that Fam19a1 knockout ( Fam19a1 -KO) mice display reduced myelin thickness in the brain. Recombinant mouse FAM19A1 (rmFAM19A1) promotes the differentiation of OLs into myelinating OLs. Proteomic interactome analyses identify DIP2A as a membrane receptor on OLs that mediates responses to neuron-derived FAM19A1. Moreover, CDK14-mediated phosphorylation of FAM19A1 at threonine 109 (pT109-FAM19A1) is required for its secretion and receptor engagement. Collectively, these findings reveal a neuron-to-OL signaling axis in which FAM19A1-DIP2A signaling supports myelin integrity in the adult brain.