Unmyelinated neurons use Neuregulin signals to promote myelination of neighboring neurons in the CNS

Abstract

The signaling mechanisms neurons use to modulate myelination of circuits in the central nervous system (CNS) are only partly understood. Through analysis of isoform-specific neuregulin1 (nrg1) mutants, we identify nrg1 type II as an important regulator of myelination in the zebrafish CNS, required for normal myelination of two classes of spinal cord neurons. Surprisingly, nrg1 type II reporter expression is prominent in unmyelinated Rohon-Beard (RB) sensory neurons, while myelination of interneurons controlling the escape response circuit is reduced in nrg1 type II mutants. Cell type-specific loss-of-function studies indicate that nrg1 type II is required in RB neurons to signal to other neurons, not oligodendrocytes, to modulate spinal cord myelination. Together, our data support a model in which unmyelinated neurons express Nrg1 type II proteins to regulate myelination of circuit partners, a mode of action that may coordinate function of circuits in the CNS involving both unmyelinated and myelinated neurons. Summary pointsO_LInrg1 type II is required for normal myelination of diverse neuronal classes in the zebrafish spinal cord C_LIO_LISurprisingly, nrg1 type II reporter expression is prominent in unmyelinated Rohon-Beard neurons C_LIO_LICell type-specific knockdown indicates that myelination of CoPA neurons requires nrg1 type II function in unmyelinated Rohon-Beard neurons C_LIO_LIThe Nrg1 receptor erbb2 is required in neurons, but not oligodendrocytes, for normal myelination C_LI