title: Targeted ablation of CRB1 and CRB2 in retinal progenitor cells mimics Leber congenital amaurosis.
abstract: Development in the central nervous system is highly dependent on the regulation of the switch from progenitor cell proliferation to differentiation, but the molecular and cellular events controlling this process remain poorly understood. Here, we report that ablation of Crb1 and Crb2 genes results in severe impairment of retinal function, abnormal lamination and thickening of the retina mimicking human Leber congenital amaurosis due to loss of CRB1 function. We show that the levels of CRB1 and CRB2 proteins are crucial for mouse retinal development, as they restrain the proliferation of retinal progenitor cells. The lack of these apical proteins results in altered cell cycle progression and increased number of mitotic cells leading to an increased number of late-born cell types such as rod photoreceptors, bipolar and Müller glia cells in postmitotic retinas. Loss of CRB1 and CRB2 in the retina results in dysregulation of target genes for the Notch1 and YAP/Hippo signaling pathways and increased levels of P120-catenin. Loss of CRB1 and CRB2 result in altered progenitor cell cycle distribution with a decrease in number of late progenitors in G1 and an increase in S and G2/M phase. These findings suggest that CRB1 and CRB2 suppress late progenitor pool expansion by regulating multiple proliferative signaling pathways.
authors: Department of Neuromedical Genetics, The Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences (KNAW), Amsterdam, The Netherlands.
authors: Lucie P
authors: LP
authors: Pellissier
authors: Celso Henrique
authors: CH
authors: Alves
authors: Peter M
authors: PM
authors: Quinn
authors: Rogier M
authors: RM
authors: Vos
authors: Naoyuki
authors: N
authors: Tanimoto
authors: Ditte M S
authors: DM
authors: Lundvig
authors: Jacobus J
authors: JJ
authors: Dudok
authors: Berend
authors: B
authors: Hooibrink
authors: Fabrice
authors: F
authors: Richard
authors: Susanne C
authors: SC
authors: Beck
authors: Gesine
authors: G
authors: Huber
authors: Vithiyanjali
authors: V
authors: Sothilingam
authors: Marina
authors: M
authors: Garcia Garrido
authors: André
authors: A
authors: Le Bivic
authors: Mathias W
authors: MW
authors: Seeliger
authors: Jan
authors: J
authors: Wijnholds
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002490:Central Nervous System / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008938:Mitosis / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D012160:Retina / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D012162:Retinal Degeneration / Q000235:genetics / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells / Q000378:metabolism
chemical_list: C453730:Crb1 protein, mouse; C568885:Crb2 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins