Developmental and Neurological Roles of DCC

DCC's role in commissural axon outgrowth is perhaps its best characterized. In the developing spinal cord, commissural neurons located dorsally extend axons ventrally using a mechanism dependent on a ventral midline structure, the floor plate. A gradient of netrin-1 is produced from the floor plate, which allows orientation of the extending axons, aiding the development of the dorsal-ventral axis of the brain and spinal column. A variety of receptors are present on the axon surface which either repel or attract axons to the midline. When membrane DCC is stimulated by netrin-1, it promotes axon progression towards the midline.

There are several other molecules also involved in the guidance of axons to and across the midline. The slit proteins have repulsive functions, as opposed to netrins, and are mediated by the transmembrane protein Robo. Axonal growth cones that are attracted to the midline by netrin/DCC signaling eventually cross the floor plate. When this occurs they lose responsiveness to netrin and become repulsed by slit/Robo signaling. This is accomplished by the formation of a DCC-Robo complex, which inhibits attractive netrin/DCC signals while allowing slit/Robo signals. Netrin also has other receptors, the UNC5 family. The UNC5 receptors have repellant migratory responses to netrin binding, and have similar effects to the slit/Robo system.

The intracellular signaling responses to netrin-1 are not yet well understood, even in neurobiology studies. Several phosphorylation events have been established, as have the involvement of several src family kinases and small GTPases, but the sequence of events has not yet been determined. DCC is also required to be recruited to lipid rafts for axon outgrowth and apoptotic signaling.
DCC is developmentally regulated, being present in most fetal tissues of the body at higher levels than what is found in adult tissues. DCC and netrin have been found to be specifically involved in the secondary migration of neural crest cells into the pancreas and developing gut structures, and may prove to be vital to other areas during fetal growth.
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