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The Journal of Neuroscience, July 1, 2001, 21(13):4740-4751

Neuregulin Signaling Regulates Neural Precursor Growth and the Generation of Oligodendrocytes In Vitro

Viviane Calaora¹, Bernard Rogister², Keren Bismuth¹, Kerren Murray¹, Heidi Brandt², Pierre Leprince², Mark Marchionni³, and Monique Dubois-Dalcq¹

¹ Neurovirologie et Régénération du Système Nerveux, Institut Pasteur, 75724 Paris, France, ² Centre de Recherches en Neurobiologie Cellulaire et Moléculaire, Université de Liège, Liège, 4020 Belgium, and ³ Cambridge NeuroScience, Inc., Norwood, Massachusetts 02139

Neuregulin 1 (Nrg-1) isoforms have been shown to influence the emergence and growth of oligodendrocytes, the CNS myelin-forming cells. We have investigated how Nrg-1 signaling of ErbB receptors specifically controls the early stages of oligodendrocyte generation from multipotential neural precursors (NPs). We show here that embryonic striatal NPs express multiple Nrg-1 transcripts and proteins as well as their specific receptors, ErbB2 and ErbB4, but not ErbB3. The major isoform synthesized by striatal NPs is a transmembrane type III isoform called cysteine-rich domain Nrg-1. To examine the biological effect of Nrg-1, we added soluble ErbB3 (sErbB3) to growing neurospheres. This inhibitor of Nrg-1 bioactivity decreased mitosis of NPs and increased their apoptosis, resulting in a significant reduction in neurosphere size and number. When NPs were induced to migrate and differentiate by adhesion of neurospheres to the substratum, the level of type III isoforms detected by RT-PCR and Western blot decreased in parallel with a reduction in Nrg-1 fluorescence intensity in differentiating astrocytes, neurons, and oligodendrocytes. Pretreatment of growing neurospheres with sErbB3 induced a threefold increase in the proportion of oligodendrocytes generated from NPs migrating out of the neurosphere. This effect was not observed with an unrelated soluble receptor. Addition of sErbB3 during NP growth and differentiation enhanced oligodendrocyte maturation as shown by expression of galactocerebroside and myelin basic protein. We propose that both type III Nrg-1 signaling and soluble ErbB receptors modulate oligodendrocyte development from NPs.

Key words: neuregulin; neural stem cells; neurosphere growth; oligodendrocyte differentiation; ErbB receptors; embryonic mouse striata

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21134740-12$05.00/0

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