beta-Neuregulin-1 is required for the in vivo development of functional Ca2+-activated K+ channels in parasympathetic neurons

The development of functional Ca2+-activated K+ channels (K-Ca) in chick ci liary ganglion (CC) neurons requires interactions with afferent preganglion ic nerve terminals. Here we show that the essential preganglionic different iation factor is an isoform of beta -neuregulin-1. beta -Neuregulin-1 trans cripts are expressed in the midbrain preganglionic Edinger-Westphal nucleus at developmental stages that coincide with or precede the normal onset of macroscopic K-Ca in CG neurons. Injection of beta -neuregulin-1 peptide int o the brains of developing embryos evoked a robust stimulation of functiona l K-Ca channels at stages before the normal appearance of these channels in CC neurons developing in vivo. Conversely, injection of a neutralizing ant iserum specific for beta -neuregulin-1 inhibited the development of K-Ca ch annels in CG neurons. Low concentrations of beta -neuregulin-1 evoked a rob ust increase in whole-cell K-Ca in CG neurons cocultured with iris target t issues. By contrast, culturing CC neurons with iris cells or low concentrat ions of beta -neuregulin-1 by themselves was insufficient to stimulate K-Ca . These data suggest that the preganglionic factor required for the develop ment of K-Ca in ciliary ganglion neurons is an isoform of beta -neuregulin- 1, and that this factor acts in concert with target-derived trophic molecul es to regulate the differentiation of excitability.