Remove Genes to Repair Nerves

06 November 2011
Posted by Ben Valsler.

Deletion of two regulatory genes allows damaged neurons to grow back in a sustained way.  This could point the way to new drug targets that encourage nerve regrowth.

Axon regeneration with PTEN and SOCS3 genes removed
This slide is the composite images from multiple sections that cover both control and injured eyes, optic nerves and the chiasm. In contrast to the control, where no regenerating axons pass the lesion site in the left, PTEN/SOCS3 double deletion allows massive optic nerve regeneration and many axons reach the chiasm.  Credit: Fang Sun

One of the major problems with repairing or re-growing damaged cells from the Central Nervous System (CNS) is the relatively huge distances the cells need to extend in order to meet their target.  There are two stages of neuron growth in development:  De novo outgrowth and connection in the developing embryo, followed by a long period of "networked growth", where the axons - the long slender projection that carries the electrical signal from one neuron to the next  - extend, maintaining their connection at either end.  As an animal grows, this second stage can result in axons far longer than anything created by the novel growth in the embryo.

If adult CNS neurons are damaged, however, the de novo methods kick in to attempt a repair.  However, this can be slow and unreliable, and doesn't really offer the sustained repair and regrowth required to regain pre-injury performance.

Writing in Nature, Zhigang He from the Children's Hospital Boston and colleagues report that deleting or suppressing two regulatory genes - called PTEN and SOCS3 - enabled adult retinal ganglion cells from the optic nerves of mice to sustainably regenerate a damaged axon.

PTEN, or Phosphatase and tensin homolog, acts as a tumour suppressor, regulating cell growth and replication, while SOCS3, Suppressor of cytokine signaling 3, regulates cell signalling.  If you remove either gene on its own, you see a little improvement in neuron regeneration, but deleting both genes together has a remarkable effect, a more than tenfold increase in the number of regenerating cells.

The researchers then looked at the pathways downstream of these genes, and identified a number of factors that were only activated in damaged nerves if these two genes were deleted.  This suggests that PTEN and SOCS3 are suppressing growth factors and pathways that promote axon growth, and although each gene acts on different pathways, there is some synergy between them.

Understanding these factors could now provide a target for treatments that would encourage the rapid and healthy regrowth of damaged nerves and achieve functional recovery.

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