Adenyl cyclase 6 is an evolutionary conserved chief regulator of peripheral nerve development and timely myelination in vertebrates

Abstract

Myelination of large caliber axons by Schwann cells and clustering of ion channels at the nodes of Ranvier enables electrical impulses to propagate rapidly along axons in the peripheral nervous system (PNS). Although several in vitro studies have reported a role for the cyclic adenosine monophosphate (cAMP) in regulating the proliferation and differentiation of Schwann cells, the identity of the in vivo key regulator of cAMP and its broad role in peripheral nerve development remains unknown. Drawing on pharmacological, genetic, molecular, and live-imaging experiments in zebrafish and mice, we find that adenyl cyclase 6, Adcy6 , albeit in synergy with Adcy5 in mice, is required within Schwann cells for timely radial sorting and myelination in the PNS, without affecting the distribution and proliferation of Schwann cells along peripheral nerves. Our analysis also shows that Adcy6 is the main driver of early Gpr126 signaling, required for timely myelin gene expression, upstream of PKA. In addition, we show that Adcy6 −/− Adcy5 −/− mice present excess mortality, severe tremor, reduced nerve size, defective nerve conduction and motor dysfunction, highlighting both axonal and glial defects. We provide evidence that Adcy6 regulates neuronal numbers, mediates axonal transport and impacts, autonomously in neurons, upon sodium channel clustering. Together, our findings identify Adcy6 as a primary driver of early and timely cAMP activity, in vivo , during the development of the PNS in vertebrates.

The authors' abstract, as published at the source. Cellular and Molecular Life Sciences, 2026 · DOI ↗