Expression of the netrin receptor UNC-5 in lamprey brain: modulation by spinal cord transection

The sea lamprey recovers from spinal cord transection by a process that involves directionally specific regeneration of axons. The mechanisms underlying this specificity are not known, but they may involve molecular cues similar to those that guide the growth of spinal cord axons during development, such as netrins and semaphorins. To test the role of guidance cues in regeneration, we cloned netrin and its receptor UNC-5 from lamprey central nervous system (CNS) and studied their expression after spinal cord transection. In situ hybridization showed that (1) mRNA for netrin is expressed in the spinal cord, primarily in neurons of the lateral gray matter and in dorsal cells; (2) mRNA for UNC-5 is expressed in lamprey reticulospinal neurons; (3) following spinal cord transection, UNC-5 message was dramatically downregulated at two weeks, during the period of axon dieback; (4) UNC-5 message was upregulated at three weeks, when many axons are beginning to regenerate; and (5) axotomy-induced expression of UNC-5 occurred primarily in neurons whose axons regenerate poorly. Because the UNC-5 receptor is thought to mediate the chemorepellent effects of netrins, netrin signaling may play a role in limiting or channeling the regeneration of certain neurons. These data strengthen the rationale for studying the role of developmental guidance molecules in CNS regeneration.