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

Mattéa J. Finelli, Kevin J. Murphy, Lei Chen, Hongyan Zou

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

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 invitro and invivo. 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.

Original languageEnglish
Pages (from-to)1592-1606
Number of pages15
JournalCell Reports
Volume3
Issue number5
DOIs
StatePublished - May 30 2013

Bibliographical note

Funding Information:
We thank Yuhan Hao and Dr. Trent Watkins for maintaining the mouse colonies and members of our laboratory for comments on the manuscript. This work was supported by the Whitehall Foundation, the Craig H. Neilsen Foundation, the Irma T. Hirschl and Monique Weill-Caulier Trusts, and NINDS (grant NS073596 to H.Z.).

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (all)

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