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NRAGE Mediates p38 Activation and Neural Progenitor Apoptosis via the Bone Morphogenetic Protein Signaling Cascade

City of Hope/Beckman Research Institute, Department of Molecular Medicine, Duarte, California,¹ Department of Medical Oncology, Catholic University, Rome, Italy,² University of Western Ontario, London, Ontario, Canada,⁴ Maine Medical Center Research Institute, Center for Regenerative Medicine, Portland, Maine³

Received 16 December 2004/ Returned for modification 18 February 2005/ Accepted 8 June 2005

Understanding the molecular events that govern neural progenitor lineage commitment, mitotic arrest, and differentiation into functional progeny are germane to our understanding of neocortical development. Members of the family of bone morphogenetic proteins (BMPs) play pivotal roles in regulating neural differentiation and apoptosis during neurogenesis through combined actions involving Smad and TAK1 activation. We demonstrate that BMP signaling is required for the induction of apoptosis of neural progenitors and that NRAGE is a mandatory component of the signaling cascade. NRAGE possesses the ability to bind and function with the TAK1-TAB1-XIAP complex facilitating the activation of p38. Disruption of NRAGE or any other member of the noncanonical signaling cascaded is sufficient to block p38 activation and thus the proapoptotic signals generated through BMP exposure. The function of NRAGE is independent of Smad signaling, but the introduction of a dominant-negative Smad5 also rescues neural progenitor apoptosis, suggesting that both canonical and noncanonical pathways can converge and regulate BMP-mediated apoptosis. Collectively, these results establish NRAGE as an integral component in BMP signaling and clarify its role during neural progenitor development.

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