Nogo is a myelin-associated protein that is expressed in the central, but not the peripheral, nervous system, and is thought to be partly responsible for the inability of central axons to regrow after injury. But three studies of Nogo-knockout mice published in Neuron, rather than clarifying the role of Nogo in preventing regeneration, have confused matters by finding different phenotypes.

Evidence from several studies has led to the view that Nogo, with other myelin-associated proteins, inhibits outgrowth of axons. Perhaps if this inhibition could be blocked or removed, injured axons in the central nervous system could regenerate. Three groups have generated mice that lack one, two or all three isoforms of Nogo, to see whether these mice show improved regeneration of central axons.

Nogo-A is the main isoform found in oligodendrocytes, so it has attracted the most attention in studies of regeneration. The first study, by Kim et al., used mice with a mutation that prevents expression of Nogo-A and B. After spinal cord injury in young adult mice, they found that the knockout mice showed increased sprouting of corticospinal axons and also improvements in motor function — a promising result.

The second study, by Simonen and colleagues, used a Nogo-A knockout mouse and found a smaller increase in axonal growth. By contrast, Zheng et al. found that neither a Nogo-A/B mutant nor a Nogo-A/B/C mutant mouse showed any improvement in axonal regeneration or sprouting after spinal cord injury.

There is no obvious explanation for the difference in results. Although Kim et al. found that sprouting was greatest in young Nogo-A/B knockout mice, rather than older adults, the mice used by Zheng and colleagues were also young. The fact that Nogo-A knockout mice show a smaller increase in sprouting than the Nogo-A/B knockouts used by Kim and colleagues could be due to a compensatory increase in Nogo-B expression following the Nogo-A mutation but the lack of regeneration in the mice used by Zheng et al. is puzzling. Clearly, much more work is needed before we will understand the role of Nogo in preventing regeneration; and a good starting point will be to find the reasons for the different phenotypes seen in these studies.