Radial glial cells and astrocytes function to support the construction and maintenance, respectively, of the cerebral cortex. However, the mechanisms that determine how radial glial cells are established, maintained, and transformed into astrocytes in the cerebral cortex are not well understood. Here, we show that neuregulin-1 (NRG-1) exerts a critical role in the establishment of radial glial cells. Radial glial cell generation is significantly impaired in NRG mutants, and this defect can be rescued by exogenous NRG-1. Down-regulation of expression and activity of erbB2, a member of the NRG-1 receptor complex, leads to the transformation of radial glial cells into astrocytes. Reintroduction of erbB2 transforms astrocytes into radial glia. The activated form of the Notch1 receptor, which promotes the radial glial phenotype, activates the erbB2 promoter in radial glial cells. These results suggest that developmental changes in NRG-1-erbB2 interactions modulate the establishment of radial glia and contribute to their appropriate transformation into astrocytes.R adial glial cells play a critical role in the construction of the mammalian brain by contributing to the formation of neurons and astrocytes and providing an instructive scaffold for neuronal migration (1-7). The establishment of radial glial cells from an undifferentiated sheet of neuroepithelium precedes the generation and migration of neurons in the cerebral cortex. During early stages of corticogenesis, radial glial cells can give rise to neurons (3-5). Subsequent neuronal cell movement in the developing mammalian cerebral cortex occurs mainly along radial glial fibers, although nonpyramidal neurons initially migrate into the cortex in a radial glial-independent manner (1, 2, 4-7).During late stages of corticogenesis, as neurogenesis and migration dwindles, the radial glial scaffolding in the telencephalon is dismantled and transformed into type 1 astrocytes (8-10). Astrocytes contribute to the emergence and maintenance of mature brain circuitry through their function as modulators of neuronal activity (11), neurogenesis (12), and as potential neuronal precursors (13). Neurodevelopmental disorders affecting the development of radial glial cells lead to faulty neuronal and glial differentiation, thus resulting in gross CNS malformations characterized by neuronal misplacement and connectivity (14). Despite their significance, the molecular signals controlling the establishment, maintenance, and transformation of radial glial cells in the developing cerebral cortex are poorly defined.Neuregulin-1 (NRG-1), a member of the NRG family of proteins, has been implicated in the differentiation of glial cells from both central and peripheral nervous systems (15, 16). In the developing CNS, NRG-1 is expressed in migrating neurons and oligodendrocyte precursors and is thought to positively influence radial glial cell function and oligodendrocyte development (17-21). NRG-1 mediates its effects via the activation of dimers of protein tyrosine kinase receptors, erbB2, ...