Targeted ablation of CRB1 and CRB2 in retinal progenitor cells mimics Leber congenital amaurosis

Lucie P Pellissier, Celso Henrique Alves, Peter M Quinn, Rogier M Vos, Naoyuki Tanimoto, Ditte M S Lundvig, Jacobus J Dudok, Berend Hooibrink, Fabrice Richard, Susanne C Beck, Gesine Huber, Vithiyanjali Sothilingam, Marina Garcia Garrido, André Le Bivic, Mathias W Seeliger, Jan Wijnholds

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    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.

    Original languageEnglish
    JournalPLoS Genetics
    Issue number12
    Publication statusPublished - 5 Dec 2013


    • Animals
    • Cell Cycle
    • Cell Differentiation
    • Cell Proliferation
    • Central Nervous System
    • Disease Models, Animal
    • Gene Expression Regulation, Developmental
    • Humans
    • Leber Congenital Amaurosis
    • Membrane Proteins
    • Mice
    • Mitosis
    • Nerve Tissue Proteins
    • Retina
    • Retinal Degeneration
    • Retinal Rod Photoreceptor Cells
    • Stem Cells
    • Journal Article
    • Research Support, Non-U.S. Gov't


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