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

PLoS Genet. 2013;9(12):e1003976. doi: 10.1371/journal.pgen.1003976. Epub 2013 Dec 5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle / genetics
  • Cell Differentiation / genetics
  • Cell Proliferation
  • Central Nervous System / growth & development
  • Central Nervous System / metabolism*
  • Central Nervous System / pathology
  • Disease Models, Animal
  • Gene Expression Regulation, Developmental
  • Humans
  • Leber Congenital Amaurosis / genetics*
  • Leber Congenital Amaurosis / metabolism
  • Leber Congenital Amaurosis / pathology
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / biosynthesis*
  • Membrane Proteins / genetics
  • Mice
  • Mitosis / genetics
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / biosynthesis*
  • Nerve Tissue Proteins / genetics
  • Retina / cytology
  • Retina / growth & development*
  • Retina / metabolism
  • Retinal Degeneration / genetics
  • Retinal Degeneration / pathology
  • Retinal Rod Photoreceptor Cells / metabolism
  • Retinal Rod Photoreceptor Cells / pathology
  • Stem Cells / metabolism


  • Crb1 protein, mouse
  • Crb2 protein, mouse
  • Membrane Proteins
  • Nerve Tissue Proteins

Grant support

This work was supported by Rotterdamse Vereniging Blindenbelangen, Landelijke St. voor Blinden en Slechtzienden, St. Blindenhulp, St. Oogfonds Nederland, St. Retina Nederland, Netherlands Institute for Neuroscience, Foundation Fighting Blindness (TA-GT-0811-0540-NIN), and The Netherlands Organisation for Health Research and Development (ZonMw grant 43200004 to JW), European Union (HEALTH-F2-2008-200234 to ALB MWS JW), The Deutsche Forschungsgemeinschaft (DFG, grants Se837/5-2, Se837/6-1, Se837/6-2, Se837/7-1 to MWS), and the German Ministry of Education and Research (BMBF, grant 0314106 to MWS), The French National Research Agency (ANR n° BLAN07-2-186738 to ALB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.