A gene regulatory network controls the binary fate decision of rod and bipolar cells in the vertebrate retina

Dev Cell. 2014 Sep 8;30(5):513-27. doi: 10.1016/j.devcel.2014.07.018. Epub 2014 Aug 21.


Gene regulatory networks (GRNs) regulate critical events during development. In complex tissues, such as the mammalian central nervous system (CNS), networks likely provide the complex regulatory interactions needed to direct the specification of the many CNS cell types. Here, we dissect a GRN that regulates a binary fate decision between two siblings in the murine retina, the rod photoreceptor and bipolar interneuron. The GRN centers on Blimp1, one of the transcription factors (TFs) that regulates the rod versus bipolar cell fate decision. We identified a cis-regulatory module (CRM), B108, that mimics Blimp1 expression. Deletion of genomic B108 by CRISPR/Cas9 in vivo using electroporation abolished the function of Blimp1. Otx2 and RORβ were found to regulate Blimp1 expression via B108, and Blimp1 and Otx2 were shown to form a negative feedback loop that regulates the level of Otx2, which regulates the production of the correct ratio of rods and bipolar cells.

MeSH terms

  • Animals
  • Cell Differentiation / physiology
  • Cell Lineage
  • Enhancer Elements, Genetic
  • Gene Expression Regulation, Developmental*
  • Gene Regulatory Networks*
  • Homeodomain Proteins / physiology
  • In Situ Hybridization, Fluorescence
  • Mice
  • Nuclear Receptor Subfamily 1, Group F, Member 2 / physiology
  • Otx Transcription Factors / physiology
  • Positive Regulatory Domain I-Binding Factor 1
  • Receptor, Notch1 / physiology
  • Retina / embryology*
  • Retinal Bipolar Cells / cytology*
  • Retinal Rod Photoreceptor Cells / cytology*
  • Transcription Factors / physiology


  • Homeodomain Proteins
  • Notch1 protein, mouse
  • Nuclear Receptor Subfamily 1, Group F, Member 2
  • Otx Transcription Factors
  • Otx2 protein, mouse
  • Prdm1 protein, mouse
  • Receptor, Notch1
  • Rorb protein, mouse
  • Transcription Factors
  • Vsx2 protein, mouse
  • Positive Regulatory Domain I-Binding Factor 1