Regulation of Schwann cell-axon interaction in nerve development: a role for Slit2 in axonal sorting

: Radial sorting of axons is a critical process in nerve development, ensuring proper segregation of axons to form myelinated and unmyelinated Schwann cell-axon units. This process is tightly regulated by signals that mediate communication between Schwann cells and the extracellular matrix, with laminin-211 being one of the key players. However, the molecular signals involved in directing Schwann cell-axon interactions are less understood, highlighting the need to identify additional molecules that mediate axon recognition and segregation. Gaining a deeper understanding of these mechanisms may shed light on the pathogenesis of genetic neuropathies. In this study, we utilized a mouse model of either sex with defects in axonal sorting, resulting from the conditional inactivation of the COP9 signalosome component Csn5 (Jab1) in Schwann cells. Transcriptome analysis was performed to identify adhesion molecules dysregulated during nerve development. Notably, we discovered that the repulsive molecule Slit2 was significantly overexpressed in Jab1-KO nerves and was particularly abundant in axon bundles with improper sorting. We demonstrated that while Slit2 is highly expressed in embryonic nerves, its expression must be precisely regulated in mature Schwann cells. Gain- and loss-of-function mutants for Slit2 further confirmed the role of Slit2 in nerve development. Transgenic mice overexpressing Slit2 displayed defects in radial sorting and hypomyelination, while Slit2 loss led to hypermyelination and misalignment of unmyelinated axons in Remak bundles. Additionally, Slit2 dysregulation interfered with nerve regeneration following cut injury. Our findings suggest that Slit2 plays a significant role in multiple stages of nerve development and some aspects of nerve regeneration.Significance Statement Nerve development and regeneration following injury depend on intricate interactions between Schwann cells, axons, and their surrounding environment. Using both gain- and loss-of-function models, we identify a critical role for the inhibitory molecule Slit2 in regulating radial axon sorting, axonal alignment, myelination, and axon regeneration.