Differential Phosphorylation of Smad1 Integrates BMP and Neurotrophin Pathways through Erk/Dusp in Axon Development

Finelli, Matt�a�J.; Murphy, Kevin�J.; Chen, Lei; Zou, Hongyan

Abstract

Sensory axon development requires concerted actions of growth factors for the precise control of axonal outgrowth and target innervation. How developing sensory neurons integrate different cues is poorly understood. We demonstrate here that Smad1 activation is required for neurotrophin-mediated sensory axon growth in vitro and in vivo. Through differential phosphorylation, Smad1 exerts transcriptional selectivity to regulate the expression and activity of Erk1 and Erk2—two key neurotrophin effectors. Specifically, bone morphogenetic proteins (BMPs) signal through carboxy-terminal phosphorylation of Smad1 (pSmad1C) to induce Erk1/2 transcription for enhanced neurotrophin responsiveness. Meanwhile, neurotrophin signaling results in linker phosphorylation of Smad1 (pSmad1L), which in turn upregulates an Erk-specific dual-specificity phosphatase, Dusp6, leading to reduced pErk1/2 and constituting a negative-feedback loop for the prevention of axon overgrowth. Together, the BMP and neurotrophin pathways form a tightly regulated signaling network with a balanced ratio of Erk1/2 and pErk1/2 to direct the precise connections between sensory neurons and peripheral targets.

• Journal Article Type: Article
• Acceptance Date: Apr 12, 2013
• Online Publication Date: May 9, 2013
• Publication Date: May 30, 2013
• Deposit Date: Jul 25, 2021
• Publicly Available Date: Jul 27, 2021
• Journal: Cell Reports
• Print ISSN: 2211-1247
• Publisher: Cell Press
• Peer Reviewed: Peer Reviewed
• Volume: 3
• Issue: 5
• Pages: 1592-1606
• DOI: https://doi.org/10.1016/j.celrep.2013.04.011
• Keywords: General Biochemistry, Genetics and Molecular Biology
• Public URL: https://nottingham-repository.worktribe.com/output/5832693
• Publisher URL: https://www.cell.com/cell-reports/fulltext/S2211-1247(13)00178-2?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124713001782%3Fshowall%3Dtrue
• Related Public URLs: https://www.sciencedirect.com/science/article/pii/S2211124713001782
• Additional Information: This article is maintained by: Elsevier; Article Title: Differential Phosphorylation of Smad1 Integrates BMP and Neurotrophin Pathways through Erk/Dusp in Axon Development; Journal Title: Cell Reports; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.celrep.2013.04.011; Content Type: article; Copyright: Copyright © 2013 The Authors. Published by Elsevier Inc.