The Role of 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase (CNP) in the Peripheral Nervous System

Abstract

In the peripheral nervous system (PNS) Schwann cells (SC) engulf, insulate and support motor and sensory axons. Nonmyelinating SC are associated with axons smaller than 1 µm in diameter, whereas myelinating SC form a compact myelin sheath around axons larger than 1 µm in diameter to enable rapid saltatory impulse propagation. During peripheral nerve regeneration motor and sensory SC express distinct trophic factors and extracellular matrix components to allow appropriate reinnervation. This implies that motor and sensory SC display a differential molecular architecture also in the intact PNS. It was unknown if differences exist with regard to the myelin sheath. Therefore, this study first aimed to identify differences between motor and sensory SC with respect to their myelin sheath composition. For this purpose, comparative proteome analyses of dorsal and ventral root myelin were performed. Numerous differences in the molecular myelin constitution, beyond the differential expression of classical myelin proteins, were observed. In particular, the noncompact myelin protein 2’,3’-cyclic nucleotide 3-phosphodiesterase (CNP) displayed substantially higher expression levels in dorsal compared to ventral roots. This suggests a differential impact of CNP for motor and sensory fibers. In the central nervous system (CNS) CNP is involved in axonal support independent of myelination and its deficiency causes a severe neurodegeneration. Hence, this study further aimed to uncover the role of CNP in the PNS and its importance for different fiber types. Immunostainings revealed that CNP is enriched in myelinating SC that ensheath small caliber motor and sensory axons. As in the CNS, CNP ablation caused a reduction in size of the noncompacted myelin compartment. Moreover, CNP deficient mice exhibited an adult onset hypermyelination of small caliber peripheral nerve fibers. In order to understand the underlying mechanism of continued myelination, MAPK/ERK and PI3K/AKT signaling pathways were investigated. Surprisingly, the activities of both pathways increased in the absence of CNP, suggesting that CNP is a negative regulator of both pathways in mature nerves. Together, CNP deficiency caused a remarkable imbalance of the noncompacted and compacted myelin compartments which was most pronounced in SC of small fibers. Noncompacted myelin is thought to serve as a transport network for trophic factors and metabolites. Therefore the reduction of this compartment may hamper axonal support, which may have caused the observed loss of predominantly small caliber axons in adult CNP deficient mice. Taken together, CNP plays a role in axonal support and postdevelopmental negative regulation of myelination and is crucial for the integrity of small to mid-sized caliber axons in the PNS. Moreover, myelinating SC display individual myelin sheath compositions according to the size of the underlying axon, which may resemble precise adjustments to axonal demands. Understanding the myelin biology of different fibers may contribute to our understanding of motor and sensory peripheral neuropathies.