Hsc70’s trip to the tip

The chaperone Hsc70 shepherds a key guanine exchange factor to the tips of growing axons, DeGeer et al. show.

As the nervous sytem takes shape during development, netrin-1 helps steer elongating axons in the right direction. After netrin-1 stimulates the receptor DCC on the axon tip, the Rho GTPase Rac1 causes the axon to extend. The guanine exchange factor Trio switches on Rac1, but researchers haven’t figured out what transports Trio within the growth cone so that it can activate Rac1 in the right location.

DeGeer et al. found that Trio pairs up with Hsc70, a member of the heat shock protein family. Depleting Hsc70 reduced the amount of Trio that reached its proper position at the edge of the growth cone, and the axons of Hsc70-deficient cells didn’t extend in response to netrin-1. The team also discovered that Hsc70 must be able to function as a chaperone for Trio to switch on Rac1, the first time this dependence has been demonstrated for a GTPase regulator.

To test Hsc70’s function in vivo, the researchers expressed a defective form of the protein in the brains of 14-day-old embryonic mice. Three days later, cortical neurons showed growth abnormalities in the animals. For instance, certain axons that normally extend to the corpus callosum, the bridge between the brain’s hemispheres, didn’t reach the structure.

Hsc70 is abundant in neurons during development, and the findings suggest that the protein hooks onto Trio and delivers it to the tips of axons. Once there, Trio can activate Rac1 and promote axon growth. The study raises the possibility that Hsc70 also offers rides to other Rho family exchange factors.