Review article

During the past 50 years, growth and differentiation molecules have been identified and shown to contribute importantly to many different biological functions. One of these, the recently discovered neuregulin (NRG) and the associated erbB receptors were first found to be important for differentiation of the peripheral nervous system, where they direct the differentiation of Schwann cells from neural crest precursors and contribute importantly to the formation of nerve-muscle synapses. More recently, these molecules have been identified as important contributors to the development of the brain. Our studies demonstrate that NRG-1 and the three erbB subunits that form functional NRG-1 receptors are present in high quantities in the brains of mammals, and they are differentially distributed. These anatomical data suggest that this signaling system is important in the mature brain. Studies by our group and others indicate that in the mature hippocampus both sustained synaptic excitation and neuronal damage increase the expression of NRG and erbB4 receptor subunits. Second, both NRG-1 and erbB4 are overexpressed in glia that surrounds βamyloid plaques in the brains of patients with Alzheimer’s disease and in a double transgenic murine model of the disease. This accumulation appears to parallel the degree of pathogenesis. Third, application of NRG-1 to differentiated hippocampal neurons induces dendritic outgrowth and elaboration and increases the expression of several neurotransmission-related genes. Fourth, in vivo microinjection of NRG-1 in the mature hippocampus enhances synaptic transmission. Together, these data indicate that NRG-1 is a pluripotent signaling system in the mature brain.