title: Loss of Bmi1 causes anomalies in retinal development and degeneration of cone photoreceptors.
abstract: Retinal development occurs through the sequential but overlapping generation of six types of neuronal cells and one glial cell type. Of these, rod and cone photoreceptors represent the functional unit of light detection and phototransduction and are frequently affected in retinal degenerative diseases. During mouse development, the Polycomb group protein Bmi1 is expressed in immature retinal progenitors and differentiated retinal neurons, including cones. We show here that Bmi1 is required to prevent post natal degeneration of cone photoreceptors and bipolar neurons and that inactivation of Chk2 or p53 could improve but not overcome cone degeneration in Bmi1(-/-) mice. The retinal phenotype of Bmi1(-/-) mice was also characterized by loss of heterochromatin, activation of tandem repeats, oxidative stress and Rip3-associated necroptosis. In the human retina, BMI1 was preferentially expressed in cones at heterochromatic foci. BMI1 inactivation in human embryonic stem cells was compatible with retinal induction but impaired cone terminal differentiation. Despite this developmental arrest, BMI1-deficient cones recapitulated several anomalies observed in Bmi1(-/-) photoreceptors, such as loss of heterochromatin, activation of tandem repeats and induction of p53, revealing partly conserved biological functions between mouse and man.
authors.affiliation: Stem Cell and Developmental Biology Laboratory, Hôpital Maisonneuve-Rosemont, 5415 Boul. l'Assomption, Montréal, Canada H1T 2M4.
authors.forename: Andrea
authors.initials: A
authors.lastname: Barabino
authors.affiliation: Stem Cell and Developmental Biology Laboratory, Hôpital Maisonneuve-Rosemont, 5415 Boul. l'Assomption, Montréal, Canada H1T 2M4.
authors.forename: Vicky
authors.initials: V
authors.lastname: Plamondon
authors.affiliation: Stem Cell and Developmental Biology Laboratory, Hôpital Maisonneuve-Rosemont, 5415 Boul. l'Assomption, Montréal, Canada H1T 2M4.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abdouh
authors.affiliation: Stem Cell and Developmental Biology Laboratory, Hôpital Maisonneuve-Rosemont, 5415 Boul. l'Assomption, Montréal, Canada H1T 2M4.
authors.forename: Wassim
authors.initials: W
authors.lastname: Chatoo
authors.affiliation: Stem Cell and Developmental Biology Laboratory, Hôpital Maisonneuve-Rosemont, 5415 Boul. l'Assomption, Montréal, Canada H1T 2M4.
authors.forename: Anthony
authors.initials: A
authors.lastname: Flamier
authors.affiliation: Stem Cell and Developmental Biology Laboratory, Hôpital Maisonneuve-Rosemont, 5415 Boul. l'Assomption, Montréal, Canada H1T 2M4.
authors.forename: Roy
authors.initials: R
authors.lastname: Hanna
authors.affiliation: Stem Cell and Developmental Biology Laboratory, Hôpital Maisonneuve-Rosemont, 5415 Boul. l'Assomption, Montréal, Canada H1T 2M4.
authors.forename: Shufeng
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Cognitive Brain Science, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, 36-3 Gengo, Morioka, Obu, Aichi 474-8522, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Motoyama
authors.affiliation: Department of Ophthalmology, Otorhinolaryngology and Cervico-Facial Surgery, Faculty of Medicine, Université Laval, Laval, Canada G1V 0A6.
authors.forename: Marc
authors.initials: M
authors.lastname: Hébert
authors.affiliation: Department of Ophthalmology, Otorhinolaryngology and Cervico-Facial Surgery, Faculty of Medicine, Université Laval, Laval, Canada G1V 0A6.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Lavoie
authors.affiliation: Stem Cell and Developmental Biology Laboratory, Hôpital Maisonneuve-Rosemont, 5415 Boul. l'Assomption, Montréal, Canada H1T 2M4 Department of Neurosciences, Université de Montréal, Montréal, Canada H3T 1J4 Department of Ophthalmology, Université de Montréal, Montréal, Canada H3T 1J4 gbernier.hmr@ssss.gouv.qc.ca.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Bernier
mesh_terms: D000818:Animals; D002460:Cell Line; D064447:Checkpoint Kinase 2 / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology*; D006570:Heterochromatin / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis / Q000235:genetics*; D018384:Oxidative Stress; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D012160:Retina / Q000196:embryology; D017949:Retinal Cone Photoreceptor Cells / Q000166:cytology* / Q000502:physiology*; D017948:Retinal Rod Photoreceptor Cells / Q000166:cytology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C489421:Bmi1 protein, mouse; D006570:Heterochromatin; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D063150:Polycomb Repressive Complex 1; D064447:Checkpoint Kinase 2; C578633:Chek2 protein, mouse; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse
keywords: Bipolar neuron; Bmi1; Cone; Degeneration; Embryonic stem cell; Human; Mouse; Photoreceptor; Polycomb; Retina; Retinal development