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The Journal of Neuroscience, November 15, 1999, 19(22):9900-9912
Altered Midline Axon Pathways and Ectopic Neurons in the Developing Hypothalamus of Netrin-1- and DCC-Deficient Mice
Michael S. Deiner and David W. Sretavan Departments of Ophthalmology and Physiology, Biomedical Sciences Program, Beckman Vision Center, University of California, San Francisco, San Francisco, California 94143-0730
Optic nerve formation in mouse involves interactions between netrin-1 at the optic disk and the netrin-1 receptor DCC (deleted in colorectal cancer) expressed on retinal ganglion cell (RGC) axons. Deficiency in either protein causes RGC pathfinding defects at the disk leading to optic nerve hypoplasia (Deiner et al., 1997). Here we show that further along the visual pathway, RGC axons in netrin-1- or DCC-deficient mice grow in unusually angular trajectories within the ventral hypothalamus. In heterozygous Seyneu mice that also have a small optic nerve, RGC axon trajectories appear normal, indicating that the altered RGC axon trajectories in netrin-1 and DCC mutants are not secondarily caused by optic nerve hypoplasia. Intrinsic hypothalamic patterning is also affected in netrin-1 and DCC mutants, including a severe reduction in the posterior axon projections of gonadotropin-releasing hormone neurons. In addition to axon pathway defects, antidiuretic hormone and oxytocin neurons are found ectopically in the ventromedial hypothalamus, apparently no longer confined to the supraoptic nucleus in mutants. In summary, netrin-1 and DCC, presumably via 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.
Key words: optic chiasm; netrin; DCC; hypothalamus; gonadotropin-releasing hormone; luteinizing hormone-releasing hormone; antidiuretic hormone; vasopressin; supraoptic nucleus; oxytocin; visual system; retinal ganglion cell; axon guidance; cell migration; diencephalon; CD44; organum vasculosum of the lamina terminalis
Copyright © 1999 Society for Neuroscience 0270-6474/99/19229900-13$05.00/0
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