Multiple adhesion molecules act together in oligodendrocyte-mediated axonal selection and myelin formation

Rapid information processing in complex organisms depends on myelin, which consists of a multilamellar membrane that tightly adheres to the axonal surface along the internode and at paranodal loops, where specialized adhesion proteins maintain axon-glial contact. Because the decision to myelinate an axon profoundly influences neuronal transmission, this process must be precisely regulated. Yet, it remains unclear which specific molecules enable oligodendrocytes to select appropriate axonal substrates for myelination. Several key myelin-associated adhesion systems have been identified, including Myelin-associated glycoprotein (Mag) and Cell Adhesion Molecule 4 (Cadm4) at the internode, as well as Contactin1 (Cntn1) at the paranode; however, these three adhesion molecules have not previously been deleted in combination. Here, using zebrafish, we systematically disrupted all three myelin-associated adhesion systems. We found that the combined loss of Mag, Cadm4, and Cntn1 severely impairs myelin initiation and destabilizes the few nascent sheaths that do form, resulting in a phenotype characterized by oligodendrocytes exhibiting membrane “stubs”. The failure to form myelin triggered cell death of early myelinating oligodendrocytes and resulted in profound hypomyelination. Our findings reveal that axonal target selection and myelin formation depend on a redundant set of adhesion molecules, and that their simultaneous loss largely abolishes myelin biogenesis.