Fast nerve transmission is made possible by the discontinuous myelin sheath that surrounds a subset of axons. Understanding the processes by which Schwann cells (SCs), the myelinating glia of the PNS, form one-to-one associations with axons during development (termed radial sorting) may eventually lead to treatments for patients with demyelinating disorders. Two papers published this month unravel a signalling cascade that is critical for radial sorting and reveal a role for the RhoGTPase rac1 in this process.

Extracellular cues, such as laminin, guide the selection and targeting of axons for myelination by SCs, and the laminin receptor 1 integrin has been shown to be crucial for radial sorting. Feltri and colleagues used mice in which 1 integrin was absent from SCs and which had impaired peripheral myelination. In neuronal cultures derived from these mice, the initial association between SCs and axons was normal, suggesting that the cause of the myelination defect lay at the next stage, when the SCs begin to extend radial processes (lamellipodia) into axon bundles. Indeed, SCs lacking 1 integrin produced reduced numbers of radial lamellipodia when grown in a laminin-coated dish.

Which signalling processes govern lamellipodia production? The RhoGTPases — which include cdc42, rac1 and rhoA — regulate cytoskeletal rearrangements, and both rac1 and cdc42 have been implicated in SC myelination. Both Feltri and Relvas's groups assayed RhoGTPase activity in mice with SCs that lacked 1 integrin and revealed a reduction in activity and membrane targeting of rac1, suggesting that rac1 activity in SCs depends on 1 integrin signalling. By contrast, cdc42 activity was unaltered or slightly increased.

The authors of both studies generated mice in which rac1 was absent from SCs. Rac1-lacking SCs had defects in the extension of lamellipodia into axon bundles, which led to a developmental delay in axon sorting. By contrast, Relvas's group showed that, although myelination was reduced in cdc42-lacking SCs, these cells were able to extend processes normally. The myelination defects in these mice were due to reduced SC precursor proliferation.

Both groups tested the effects of rac1 on lamellipodia production by plating rac1-lacking SCs on laminin, which revealed defects in lamellipodia production similar to those observed in the 1 integrin-lacking SCs. Likewise, when Feltri's group used a specific rac1 inhibitor on cultured SCs, the number of radial lamellipodia produced was reduced. Feltri and colleagues confirmed the key role of rac1 activity in the effects of 1 integrin by overexpressing constitutively active rac1 in 1 integrin-lacking SCs; using this strategy they could rescue some of the deficits in radial sorting caused by the absence of 1 integrin.

These studies suggest that rac1 activity, regulated by 1 integrin signalling, is crucial for normal lamellipodia extension in SCs and, therefore, for radial axon sorting. More work is needed to understand the signalling that underlies the selection by an SC of the axon it will myelinate and to delineate the pathways involved in PNS myelination.

Author: Katherine Whalley - Copyright © 2007 Nature Publishing Group, a division of MacMillan Publishers Limited; used with permission