C-type natriuretic peptide is a Schwann cell-derived factor for development and function of sensory neurons

Cyclic GMP (cGMP) is known to play important roles for neuronal development and neurite pathfinding. However, the regulatory mechanism that governs the synthesis of cGMP in the nervous system is not well defined. In the present study, we examined the role of C-type natriuretic peptide (CNP), which increases intracellular cGMP upon binding to its receptor, guanylyl cyclase (GC)-B, in the peripheral nervous system. Immunohistochemistry revealed that CNP is demonstrated in Schwann cells, whereas GC-B mRNA is highly expressed in dorsal root ganglion (DRG) neurones. In cultured DRG neurones, GC-B was demonstrated in dendrites of TrkA-positive cells, where it co-exists with cGMP-dependent protein kinase I (cGKI), the major intracellular mediator of cGMP actions. Addition of CNP in the culture medium increased the density of fine neurites, which was accompanied by the increase in phosphorylation of vasodilator-stimulated phosphoprotein, a cGKI substrate. Furthermore, in mice deficient for the CNP gene (CNP-KO), the numbers of TrkA-positive DRG neurones were diminished. Likewise, there were much less cGKI-positive neurones in DRG and cGKI-positive fibres in the dorsal spinal cord of CNP-KO than wild-type mice. Finally, the bone deformity-rescued CNP-KO mice displayed a decreased response to formalin-induced pain compared to wild-type. Taken together, these results suggest that CNP is derived from Schwann cells and plays an important role for the development and function of nociceptive sensory neurones.