Regulation of Schwann Cell–Axon Interactions in Nerve Development: The Role of Slit2 in Axonal Sorting

Abstract

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 regulated by signals mediating communication between Schwann cells and the extracellular matrix, with laminin-211 as a key component. 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.