title: Proper patterning of the optic fissure requires the sequential activity of BMP7 and SHH.
abstract: The optic disc develops at the interface between optic stalk and retina, and enables both the exit of visual fibres and the entrance of mesenchymal cells that will form the hyaloid artery. In spite of the importance of the optic disc for eye function, little is known about the mechanisms that control its development. Here, we show that in mouse embryos, retinal fissure precursors can be recognised by the expression of netrin 1 and the overlapping distribution of both optic stalk (Pax2, Vax1) and ventral neural retina markers (Vax2, Raldh3). We also show that in the absence of Bmp7, fissure formation is not initiated. This absence is associated with a reduced cell proliferation and apoptosis in the proximoventral quadrant of the optic cup, lack of the hyaloid artery, optic nerve aplasia, and intra-retinal misrouting of RGC axons. BMP7 addition to organotypic cultures of optic vesicles from Bmp7-/- embryos rescues Pax2 expression in the ventral region, while follistatin, a BMP7 antagonist, prevents it in early, but not in late, optic vesicle cultures from wild-type embryos. The presence of Pax2-positive cells in late optic cup is instead abolished by interfering with Shh signalling. Furthermore, SHH addition re-establishes Pax2 expression in late optic cups derived from ocular retardation (or) embryos, where optic disc development is impaired owing to the near absence of SHH-producing RGC. Collectively, these data indicate that BMP7 is required for retinal fissure formation and that its activity is needed, before SHH signalling, for the generation of PAX2-positive cells at the optic disc.
authors.affiliation: Departamento de Neurobiología del Desarrollo, Instituto Cajal, CSIC, Dr Arce 37, Madrid 28002, Spain.
authors.forename: Julian
authors.initials: J
authors.lastname: Morcillo
authors.forename: Juan Ramon
authors.initials: JR
authors.lastname: Martínez-Morales
authors.forename: Françoise
authors.initials: F
authors.lastname: Trousse
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Fermin
authors.forename: Jane C
authors.initials: JC
authors.lastname: Sowden
authors.forename: Paola
authors.initials: P
authors.lastname: Bovolenta
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000378:metabolism; D019521:Body Patterning / Q000235:genetics; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D005123:Eye / Q000196:embryology / Q000378:metabolism; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009414:Nerve Growth Factors / Q000378:metabolism; D000075388:Netrin-1; D009479:Neuropeptides / Q000378:metabolism; D009898:Optic Disk / Q000196:embryology* / Q000378:metabolism; D009900:Optic Nerve / Q000196:embryology / Q000378:metabolism; D051762:PAX2 Transcription Factor / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D009414:Nerve Growth Factors; D009479:Neuropeptides; C000617353:Ntn1 protein, mouse; D051762:PAX2 Transcription Factor; C497319:Pax2 protein, mouse; C465570:Shh protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C485177:Vax1 protein, mouse; C120595:Vax2 protein, mouse; C088975:Vsx2 protein, mouse; D000075388:Netrin-1; D000445:Aldehyde Oxidoreductases; C470579:RALDH2 protein, mouse