A Notch Above ErbB

Abstract

Radial glia are present early in development and help guide neuronal migration in the developing brain, which is essential for normal brain function. In the cerebellum, the formation of radial glia depends on contact with neurons and involves Notch1 and ErbB signaling. The mechanisms whereby neuronal contact initiates radial glial development, however, and the relationship between these two pathways are unclear. Patten et al. used cocultures to show that cerebellar granule cells stimulated Notch-dependent activation of a gene reporter expressed in cerebellar glia, as well as development of radial glial morphology. Glial expression of a constitutively active form of Notch1 also promoted radial morphology, as did coculture with fibroblasts expressing the Notch ligand Jagged1 or exposure to the ErbB ligand neuregulin (NRG). Expression in glia of dominant-negative forms of Notch1 or the ErbB receptor blocked the ability of granule cells to stimulate radial morphology, whereas a dominant-negative form of the Notch signal transducer Suppressor of Hairless (SuH) did not. Experiments involving various dominant-negatives and gene reporters indicated that Notch1 signaling was upstream of ErbB signaling and that granule cell (and Notch1)-dependent transcriptional activation of brain lipid-binding protein (BLBP, a protein expressed by radial glia)--but not of Erb2--depended on SuH. This suggests that Notch1 promotes radial glial differentiation through at least two distinct signaling pathways. The authors propose a model in which sequential activation of Notch1 and ErbB signaling pathways are required for radial glial development and suggest that they may also act in tandem in other developmental events.B. A. Patten, J. M. Peyrin, G. Weinmaster, G. Corfas, Sequential signaling through Notch1 and ErbB receptors mediates radial glia differentiation. J. Neurosci. 23, 6132-6140 (2003). [Abstract] [Full Text]