title: Altered midline axon pathways and ectopic neurons in the developing hypothalamus of netrin-1- and DCC-deficient mice.
abstract: 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.
authors.affiliation: Departments of Ophthalmology and Physiology, Biomedical Sciences Program, Beckman Vision Center, University of California, San Francisco, San Francisco, California 94143-0730, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Deiner
authors.forename: D W
authors.initials: DW
authors.lastname: Sretavan
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D000831:Animals, Newborn; D001370:Axonal Transport; D001369:Axons / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000502:physiology*; D000075389:DCC Receptor; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D005314:Embryonic and Fetal Development; D005136:Eye Proteins; D005260:Female; D019922:GAP-43 Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D016163:Genes, DCC; D013006:Growth Hormone / Q000097:blood; D018398:Homeodomain Proteins; D007031:Hypothalamus / Q000002:abnormalities / Q000196:embryology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000075386:Netrin Receptors; D000075388:Netrin-1; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D009897:Optic Chiasm / Q000196:embryology / Q000502:physiology; D009900:Optic Nerve / Q000002:abnormalities / Q000502:physiology*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins; D012165:Retinal Ganglion Cells / Q000473:pathology / Q000502:physiology*; D025521:Tumor Suppressor Proteins; D014795:Visual Pathways / Q000196:embryology / Q000502:physiology*
chemical_list: D015815:Cell Adhesion Molecules; D000075389:DCC Receptor; D004268:DNA-Binding Proteins; C501910:Dcc protein, mouse; D005136:Eye Proteins; D019922:GAP-43 Protein; D018398:Homeodomain Proteins; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; C000617353:Ntn1 protein, mouse; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; D000324:Adrenocorticotropic Hormone; D013006:Growth Hormone