title: Foxg1-Cre Mediated Lrp2 Inactivation in the Developing Mouse Neural Retina, Ciliary and Retinal Pigment Epithelia Models Congenital High Myopia.
abstract: Myopia is a common ocular disorder generally due to increased axial length of the eye-globe. Its extreme form high myopia (HM) is a multifactorial disease leading to retinal and scleral damage, visual impairment or loss and is an important health issue. Mutations in the endocytic receptor LRP2 gene result in Donnai-Barrow (DBS) and Stickler syndromes, both characterized by HM. To clearly establish the link between Lrp2 and congenital HM we inactivated Lrp2 in the mouse forebrain including the neural retina and the retinal and ciliary pigment epithelia. High resolution in vivo MRI imaging and ophthalmological analyses showed that the adult Lrp2-deficient eyes were 40% longer than the control ones mainly due to an excessive elongation of the vitreal chamber. They had an apparently normal intraocular pressure and developed chorioretinal atrophy and posterior scleral staphyloma features reminiscent of human myopic retinopathy. Immunomorphological and ultrastructural analyses showed that increased eye lengthening was first observed by post-natal day 5 (P5) and that it was accompanied by a rapid decrease of the bipolar, photoreceptor and retinal ganglion cells, and eventually the optic nerve axons. It was followed by scleral thinning and collagen fiber disorganization, essentially in the posterior pole. We conclude that the function of LRP2 in the ocular tissues is necessary for normal eye growth and that the Lrp2-deficient eyes provide a unique tool to further study human HM.
authors.affiliation: INSERM, U968, Paris, F-75012, France; UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS, UMR_7210, Paris, F-75012, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Cases
authors.affiliation: INSERM, U968, Paris, F-75012, France; UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS, UMR_7210, Paris, F-75012, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Joseph
authors.affiliation: CNRS, UMR_6270, PISSARO Proteomics Platform, Institute for Research and Innovation in Biomedicine, Rouen University Hospital, Rouen, F-76821, France; INSERM, U905, PISSARO Proteomics Platform, Institute for Research and Innovation in Biomedicine, Rouen University Hospital, Rouen, F-76821, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Obry
authors.affiliation: Centre de NeuroImagerie de Recherche, Paris, F-75013, France.
authors.forename: Mathieu D
authors.initials: MD
authors.lastname: Santin
authors.affiliation: INSERM, U968, Paris, F-75012, France; UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS, UMR_7210, Paris, F-75012, France.
authors.forename: Sirine
authors.initials: S
authors.lastname: Ben-Yacoub
authors.affiliation: INSERM, U968, Paris, F-75012, France; UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS, UMR_7210, Paris, F-75012, France; Centre Hospitalier National d'Ophthalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, F-75012, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Pâques
authors.affiliation: INSERM, U968, Paris, F-75012, France; UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS, UMR_7210, Paris, F-75012, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Amsellem-Levera
authors.affiliation: Grupo de Neurobiologia del Desarollo-GNDe, Hospital Nacional de Parapléjicos, Toledo, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Bribian
authors.affiliation: INSERM, U968, Paris, F-75012, France; UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS, UMR_7210, Paris, F-75012, France.
authors.forename: Manuel
authors.initials: M
authors.lastname: Simonutti
authors.affiliation: INSERM, U968, Paris, F-75012, France; UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS, UMR_7210, Paris, F-75012, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Augustin
authors.affiliation: Sanofi-Ophthalmology, Paris, F-75012, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Debeir
authors.affiliation: INSERM, U968, Paris, F-75012, France; UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS, UMR_7210, Paris, F-75012, France; Centre Hospitalier National d'Ophthalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, F-75012, France.
authors.forename: José Alain
authors.initials: JA
authors.lastname: Sahel
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, D-13125, Germany.
authors.forename: Annabel
authors.initials: A
authors.lastname: Christ
authors.affiliation: Grupo de Neurobiologia del Desarollo-GNDe, Hospital Nacional de Parapléjicos, Toledo, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: de Castro
authors.affiliation: Centre de NeuroImagerie de Recherche, Paris, F-75013, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Lehéricy
authors.affiliation: CNRS, UMR_6270, PISSARO Proteomics Platform, Institute for Research and Innovation in Biomedicine, Rouen University Hospital, Rouen, F-76821, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Cosette
authors.affiliation: INSERM, U968, Paris, F-75012, France; UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS, UMR_7210, Paris, F-75012, France.
authors.forename: Renata
authors.initials: R
authors.lastname: Kozyraki
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D049109:Cell Proliferation; D002924:Ciliary Body / Q000378:metabolism*; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D007429:Intraocular Pressure; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009154:Mutation; D047728:Myopia, Degenerative / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009900:Optic Nerve / Q000378:metabolism; D010641:Phenotype; D016548:Prosencephalon / Q000378:metabolism; D012160:Retina / Q000196:embryology / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000196:embryology / Q000378:metabolism*; D012590:Sclera / Q000473:pathology
chemical_list: D051858:Forkhead Transcription Factors; C489565:Foxg1 protein, mouse; D026561:Low Density Lipoprotein Receptor-Related Protein-2; C055127:Lrp2 protein, mouse; D009419:Nerve Tissue Proteins