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Cross Talk between Notch and Growth Factor/Cytokine Signaling Pathways in Neural Stem Cells

Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039,¹ Departments of Pediatrics and Neurosurgery, University of Cincinnati College of Medicine, 3125 Eden Avenue, Cincinnati, Ohio 45267-0521,² Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, 3-415 Nihonbashi, Chuo-ku, Tokyo 103-0027, Japan³

Received 29 January 2007/ Returned for modification 25 February 2007/ Accepted 11 March 2007

Precise control of proliferation and differentiation of multipotent neural stem cells (NSCs) is crucial for proper development of the nervous system. Although signaling through the cell surface receptor Notch has been implicated in many aspects of neural development, its role in NSCs remains elusive. Here we examined how the Notch pathway cross talks with signaling for growth factors and cytokines in controlling the self-renewal and differentiation of NSCs. Both Notch and growth factors were required for active proliferation of NSCs, but each of these signals was sufficient and independent of the other to inhibit differentiation of neurons and glia. Moreover, Notch signals could support the clonal self-renewing growth of NSCs in the absence of growth factors. This growth factor-independent action of Notch involved the regulation of the cell cycle and cell-cell interactions. During differentiation of NSCs, Notch signals promoted the generation of astrocytes in collaboration with ciliary neurotrophic factor and growth factors. Their cooperative actions were likely through synergistic phosphorylation of signal transducer and activator of transcription 3 on tyrosine at position 705 and serine at position 727. Our data suggest that distinct intracellular signaling pathways operate downstream of Notch for the self-renewal of NSCs and stimulation of astrogenesis.

Published ahead of print on 19 March 2007.