The E3 ubiquitin ligase Nedd4 fosters developmental myelination in the mouse central and peripheral nervous system

Ubiquitination is a major post‐translational regulatory mechanism that tunes numerous aspects of ubiquitinated target proteins, including localization, stability, and function. During differentiation and myelination, Oligodendrocytes (OLs) in the central nervous system and Schwann cells (SCs) in the peripheral nervous system undergo major cellular changes, including the tightly controlled production of large and accurate amounts of proteins and lipids. Such processes have been implied to depend on regulatory aspects of ubiquitination, with E3 ubiquitin ligases being generally involved in the selection of specific ubiquitination substrates by ligating ubiquitin to targets and granting target selectivity. In this study, we have used multiple transgenic mouse lines to investigate the functional impact of the E3 ubiquitin ligase Nedd4 in the OL‐ and SC‐lineages. Our findings in the developing spinal cord indicate that Nedd4 is required for the correct accumulation of differentiated OLs and ensures proper myelination, supporting and further expanding previously suggested conceptual models. In sciatic nerves, we found that Nedd4 is required for timely radial sorting of axons by SCs as a pre‐requirement for correct onset of myelination. Moreover, Nedd4 ensures correct myelin thickness in both SCs and spinal cord OLs. Main Points Developing spinal cord: Nedd4 is required for accurate accumulation of differentiated oligodendrocytes and proper myelination. Developing sciatic nerve: Nedd4 is required for correct Schwann cell numbers, timely radial sorting, and proper myelination.