Neuregulins (NRGs), a large group of structurally related signaling proteins, are likely to have important roles in the development, maintenance and repair of the nervous system and other selected tissues. We have demonstrated, by using the major form of NRG cloned from the mouse cerebellum that both the soluble form and the membrane anchored form of NRG may serve different functions in synaptogenesis. The soluble form of NRG was produced by proteolytic cleavage of the membrane anchored form of NRG. The proteolytic cleavage was promoted by protein kinase activation. The cleaved form of NRG transsynaptically regulated the expression of the NMDA (Nmethyl-D-aspartate) receptor subunit NR2C as neurallyderived factors, whereas the membrane anchored form of NRG showed a homophilic binding activity between NRGβ€1s. In adult mice the membrane anchored form of NRG was concentrated in neuro-terminals of both granule cells and pontocerebellar mossy fibers. The fact that NRG can be functionally viewed as cell recognition molecules as well as neurotrophic agents suggests new possibilities for the important class of molecules.