Neuregulin-2 is developmentally regulated and targeted to dendrites of central neurons

Neuregulin-1 (NRG-1) regulates numerous aspects of neural development and synaptic plasticity; the functions of NRG-2 and NRG-3 are presently unknown. As a first step toward understanding how NRGs contribute to distinct aspects of neural development and function, we characterized their regional and subcellular expression patterns in developing brain. The expression of NRG-1-3 mRNAs was compared postnatally (P0, P7, adult) by using in situ hybridization. NRG-1 expression is highest at birth, whereas NRG-2 mRNA levels increase with development; expression of both genes is restricted to distinct brain regions. In contrast, NRG-3 transcripts are abundant in most brain regions throughout development. NRG-2 antibodies were generated to analyze protein processing, expression, and subcellular distribution. As with NRG-1, the transmembrane NRG-2 proprotein is proteolytically processed in transfected HEK 293 cells and in neural tissues, and its ectodomain is exposed and accumulates on the neuron surface. Despite the structural similarities between NRG-1 and NRG-2, we unexpectedly found that NRG-2 colocalizes with MAP2 in proximal primary dendrites of hippocampal neurons in culture and in vivo, although it is not detectable in axons or in axon terminals. These findings were confirmed with NRG-2 ectodomain antisera and epitope-tagged recombinant protein. In cerebellum, NRG-2 colocalizes with calbindin in proximal dendrites and soma of Purkinje cells. In contrast, NRG-1 is highly expressed in axons of dissociated hippocampal neurons, as well as in somas and dendrites. The distinct temporal, regional, and subcellular expression of NRG-2 suggests its unique and nonredundant role in neural function.