RESUMO
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.
Assuntos
Moléculas de Adesão Celular/fisiologia , Proteínas de Homeodomínio , Hipotálamo/fisiologia , Fatores de Crescimento Neural/fisiologia , Neurônios/fisiologia , Nervo Óptico/fisiologia , Receptores de Superfície Celular/fisiologia , Células Ganglionares da Retina/fisiologia , Proteínas Supressoras de Tumor , Vias Visuais/fisiologia , Hormônio Adrenocorticotrópico/sangue , Animais , Animais Recém-Nascidos , Transporte Axonal , Axônios/fisiologia , Moléculas de Adesão Celular/genética , Receptor DCC , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Desenvolvimento Embrionário e Fetal , Proteínas do Olho , Feminino , Proteína GAP-43/deficiência , Proteína GAP-43/genética , Proteína GAP-43/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Genes DCC , Hormônio do Crescimento/sangue , Hipotálamo/anormalidades , Hipotálamo/embriologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Crescimento Neural/deficiência , Fatores de Crescimento Neural/genética , Receptores de Netrina , Netrina-1 , Neurônios/patologia , Quiasma Óptico/embriologia , Quiasma Óptico/fisiologia , Nervo Óptico/anormalidades , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados , Receptores de Superfície Celular/deficiência , Receptores de Superfície Celular/genética , Proteínas Repressoras , Células Ganglionares da Retina/patologia , Vias Visuais/embriologiaRESUMO
Embryonic retinal ganglion cell (RGC) 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-1- 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.
