Altered Midline Axon Pathways and Ectopic Neurons in the Developing Hypothalamus of Netrin-1- and DCC-Deficient Mice

• Published in: The Journal of neuroscience Vol. 19; no. 22; pp. 9900 - 9912
• Main Authors: Deiner, Michael S, Sretavan, David W
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 15.11.1999; Society for Neuroscience
• Subjects: Adrenocorticotropic Hormone - blood; Animals; Animals, Newborn; Axonal Transport; Axons - physiology; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - physiology; DCC Receptor; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Embryonic and Fetal Development; Eye Proteins; Female; GAP-43 Protein - deficiency; GAP-43 Protein - genetics; GAP-43 Protein - physiology; Gene Expression Regulation, Developmental; Genes, DCC; Growth Hormone - blood; Homeodomain Proteins; Hypothalamus - abnormalities; Hypothalamus - embryology; Hypothalamus - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Growth Factors - deficiency; Nerve Growth Factors - genetics; Nerve Growth Factors - physiology; Netrin Receptors; Netrin-1; Neurons - pathology; Neurons - physiology; Optic Chiasm - embryology; Optic Chiasm - physiology; Optic Nerve - abnormalities; Optic Nerve - physiology; Paired Box Transcription Factors; PAX6 Transcription Factor; Receptors, Cell Surface - deficiency; Receptors, Cell Surface - genetics; Receptors, Cell Surface - physiology; Repressor Proteins; Retinal Ganglion Cells - pathology; Retinal Ganglion Cells - physiology; Tumor Suppressor Proteins; Visual Pathways - embryology; Visual Pathways - physiology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.19-22-09900.1999

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 (). 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 Sey(neu) 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.