The signalling pathway activated by the RAF mitogen protein kinase (BRAF/MAP2K/ERK) is crucially involved in axon growth in the nervous system during the development of an organism. Furthermore, it is assumed that this pathway is also important for the regeneration of axons in the mature PNS and CNS, especially after stimulation by growth factors. In a paper published last year in Science Translational Medicine, Francesco Boato and colleagues show that selective activation of B-Raf in lamina V neurons in the motor cortex significantly improves the regeneration of long axons in the pyramidal tract. These axons normally regenerate at a very low rate only, but their growth can be stimulated by genetic manipulation in animal models.
The experiments now carried out are based on observations in cell cultures in which high-frequency stimulation (depolarisation) of hippocampal neurons activates the BRAF/MAP2K/ERK signalling pathway and neurite growth. In analogy to this method, repetitive transcranial magnetic stimulation (rTMS) was used in the current study after a spinal cord injury in the mouse. rTMS is a non-invasive technique that generates an electric field by induction and is already used to treat severe depressive disorders and pain syndromes. In doing so, rTMS increases the BDNF level in the brain, strengthens synaptic plasticity and improves energy metabolism and thus also memory (see my blog post from 12 January 2023).
However, it is unclear whether rTMS can really promote the regeneration of injured nerve fibres and the sprouting of intact axons in the CNS after injury. In their work, the authors convincingly demonstrated that activation of the BRAF/MAP2K/ERK signalling pathway by genetic manipulation or by high-frequency rTMS promotes robust sprouting of lesioned axons in the spinal cord and thus improves the fine motor skills of affected animals. Using gene expression analysis, they detected a number of transcription factors that correlated with successful axon regeneration in zebrafish, i.e. presumably B-Raf stimulation activates an intrinsic, proregenerative genetic programme that can be induced by BDNF, but also by TGFs and FGFs (these factors were all detectable to a greater extent in B-Raf-activated neurons of the pyramidal tract).
The present results therefore open the door for the development of stimulation protocols to induce axonal regeneration in the CNS. If these studies are successful, rTMS will certainly be used as a non-invasive and low-risk treatment option, possibly in combination with other interventions, in paraplegic patients.
Reference:
Boato F, Guan X, Zhu Y, ..., Edwards DJ, Zhong J (2023) Activation of MAP2K signalling by genetic engineering or HF-rTMS promotes corticospinal axon sprouting and functional regeneration. Science Translational Medicine 15:eabq6885
Image credit: Fig. 1 from Boato et al. (2023) Science Translational Medicine 15:eabq6885