Binding of DCC by netrin-1 to mediate axon guidance independent of adenosine A2B receptor activation

Netrins stimulate and orient axon growth through a mechanism requiring rece ptors of the DCC family. it has been unclear, however, whether DCC proteins are involved directly in signaling or are mere accessory proteins in a rec eptor complex. Further, although netrins bind cells expressing DCC, direct binding to DCC has not been demonstrated. Here we show that netrin-1 binds DCC and that the DCC cytoplasmic domain fused to a heterologous receptor ec todomain can mediate guidance through a mechanism involving derepression of cytoplasmic domain multimerization. Activation of the adenosine A2B recept or, proposed to contribute to netrin effects on axons, is not required for rat commissural axon outgrowth or Xenopus spinal axon attraction to netrin- 1: Thus, DCC plays a central role in netrin signaling of axon growth and gu idance independent of A2B receptor activation.