BMP4/Smad1 Signalling Promotes Spinal Dorsal Column Axon Regeneration and Functional Recovery After Injury

Research output: Contribution to journalArticle

Authors

Colleges, School and Institutes

External organisations

  • Neuroscience and Ophthalmology, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK. z.ahmed.1@bham.ac.uk.

Abstract

Signalling through the BMP4/Smad1 pathway promotes corticospinal tract axon regeneration and functional recovery in mice. However, unlike humans and rats, mice do not cavitate. Here, we investigated if activation of the BMP4/Smad1 pathway promotes axon regeneration and functional recovery in a rat model that cavitates. We show that dorsal root ganglion neurons (DRGN) in injury models, including the non-regenerating dorsal column (DC) and the regenerating sciatic nerve (SN) crush and preconditioning (p) SN + DC (pSN + DC) paradigms, regulate the BMP4/Smad1 signalling pathway. For example, mRNA expression of positive regulators of the BMP4/Smad1 pathway was highly up-regulated whilst negative regulators were significantly down-regulated in DRGN in the regenerating SN and pSN + DC models compared to non-regenerating DC models, matched by concomitant changes in protein expression detected in DRGN by immunohistochemistry. BMP4 peptide promoted significant DRGN survival and disinhibited neurite outgrowth in vitro, whilst AAV-BMP4 delivery in vivo stimulated DC axon regeneration and functional recovery in a model that cavitates. Our results show that activation of the BMP4/Smad1 pathway is a potential therapeutic target in the search for axon regenerative signalling pathways in the CNS.

Details

Original languageEnglish
JournalMolecular Neurobiology
Early online date28 Mar 2019
Publication statusE-pub ahead of print - 28 Mar 2019

Keywords

  • Spinal cord injury, BMP4, Smad1, Dorsal root ganglion neurons, Dorsal column, Axon regeneration