The intracellular domain of Nrg-1 (red) moves to the nucleus (blue) upon erbB treatment (right).

On page 1133, Bao et al. demonstrate that a neuronal growth factor signals to neighboring cells while also communicating back to the nucleus of its own cell. This two-way signaling is necessary to maintain neuronal survival.

In the forward direction, either a soluble or membrane-bound form of the Nrg-1 growth factor activates erbB receptor tyrosine kinases on a variety of adjacent cells. The Nrg-1/erbB partnership is well known to control responses in the erbB-expressing cells, such as epithelial cell motility and proliferation, through MAP kinase pathways. Now, the target cells are shown to talk back to neurons that express membrane-bound Nrg-1 via the same erbB–Nrg-1 complex.Bao et al. show that treatment with soluble erbB protects Nrg-1–expressing neurons from cell death in vitro. The protective activity appears to stem from Nrg-1's ability to regulate transcription of apoptotic genes, including BAK and RIP, whose expression levels were repressed by treatment with erbB. Membrane-bound Nrg-1 was cleaved by a γ-secretase–like activity in response to erbB treatment, thus releasing the Nrg-1 intracellular domain, which moved to the nucleus. Although Nrg-1 has not been shown to bind to DNA, the authors demonstrate that it does has transactivating activity on a reporter construct, and preliminary evidence indicates it may interact with zinc finger–containing transcription factors. ▪