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.
Highlights
Several signalling pathways have been associated with axon regeneration after spinal cord injury (SCI)
We show that bone morphogenetic protein 4 (BMP4)/Smad1 is activated when dorsal root ganglion neuron (DRGN) axons regenerate after an sciatic nerve (SN) and pre-conditioning SN lesion (pSN) + dorsal column (DC) lesions, BMP4 peptide promotes disinhibited DRGN neurite outgrowth in the presence of inhibitory CNS myelin extracts (CME), whilst BMP4 overexpression in DRGN in vivo enhances DC axon regeneration and promotes functional recovery in adult rats, despite the presence of spinal cord cavities
Microarray data showed that the levels of mRNA for smad1, smad2, smad4, smad5, smad8 and bmp4 were all up-regulated between 2.0- and 6.7-fold compared to sham controls, whilst noggin was 2-fold down-regulated, in the DRG from both the SN and pSN + DC models (Table 3), but there was no change in these mRNA levels in DRG from the DC model
Summary
Several signalling pathways have been associated with axon regeneration after spinal cord injury (SCI) These include the phophoinositide-3-kinase (PI3K) and extracellular receptor kinase (ERK) pathways that are essential for axon assembly and neurotrophin-induced axonal branching [1,2,3]. The PI3KAkt pathway regulates local protein synthesis via the mammalian target of rapamycin (mTOR) signalling pathway with adult neurons requiring mTOR signalling to promote axon regeneration [4]. It is not known if mTOR signalling plays a role in the regeneration of ascending long-tract dorsal root ganglion neuron (DRGN) dorsal column (DC) projections, but an mTOR independent pathway is implicated, since pSN promotes DC axon regeneration [5, 6]. (1) PI3K/Akt induces nuclear localisation of BMP4-activated Smad and regulates Smad induction of axon regeneration-related transcription factors and (2) BMP4 activates Akt by suppression of PTEN, stimulation of MAPK and autocrine induction of growth factor secretion [11, 12]
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