| During development, embryonic retinal ganglion cell (RGQ axons must extend toward and grow through the optic disc to exit the eye into the optic nerve. In the embryonic mouse eye, we found that immunoreactivity for the axon guidance molecule netrin-1 was specifically on neuroepithelial cells at the disk surrounding exiting RGC axons, and RGC axons express the netrin receptor, DCC (deleted in colorectal cancer). In vitro, anti-DCC antibodies reduced RGC neurite outgrowth responses to netrin-1. In netrin-l- and DCC-deficient embryos, RGC axon pathfinding to the disc was unaffected; however, axons failed to exit into the optic nerve, resulting in optic nerve hypoplasia. Thus, netrin-1 through DCC appears to guide RGC axons locally at the optic disc rather than at long range, apparently reflecting the localization of netrin-1 protein to the vicinity of netrin-1 producing cells at the optic disc.;Further along the visual pathway, RGC axons in netrin-1 or DCC deficient mice grow in unusually angular trajectories within the ventral hypothalamus, often forming the optic chiasm in an abnormally posterior position. In heterozygous Seyneu mice which also have small optic nerves, RGC axon trajectories appear normal indicating the altered RGC axon trajectories in netrin-1 and DCC mutants are not secondarily due to optic nerve hypoplasia. Intrinsic hypothalamic patterning is also affected in netrin-1 and DCC mutants including a severe reduction in posterior axon projections of gonadotropin-releasing hormone neurons. In addition to axon pathway defects in mutants, antidiuretic hormone and oxytocin neurons are found ectopically in the ventromedial hypothalamus, apparently no longer confined to the supraoptic nucleus. In sum, netrin-1 and DCC, presumably through direct interactions, govern both axon pathway formation and neuronal position during hypothalamic development and loss of netrin-1 or DCC function affects both visual and neuroendocrine systems. Netrin protein localization also indicates that unlike in more caudal CNS, guidance about the hypothalamic ventral midline does not require midline expression of netrin.;Optic nerve hypoplasia and hypothalamic developmental abnormalities can now be added to corpus callosum defects in netrin-1 and DCC mutant mice. This trio of seemingly disparate phenotypes is reminiscent of the human congenital multisystem syndrome of septo-optic dysplasia. |
