title: A gene regulatory network controls the binary fate decision of rod and bipolar cells in the vertebrate retina.
abstract: 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.
authors.affiliation: Department of Genetics and Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston, MA 02115, USA.
authors.forename: Sui
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Genetics and Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Cem
authors.initials: C
authors.lastname: Sengel
authors.affiliation: Department of Biology, The City College of New York, City University of New York, New York, NY 10031, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Emerson
authors.affiliation: Department of Genetics and Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston, MA 02115, USA. Electronic address: cepko@genetics.med.harvard.edu.
authors.forename: Constance L
authors.initials: CL
authors.lastname: Cepko
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000502:physiology; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D057095:Nuclear Receptor Subfamily 1, Group F, Member 2 / Q000502:physiology; D051857:Otx Transcription Factors / Q000502:physiology; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051881:Receptor, Notch1 / Q000502:physiology; D012160:Retina / Q000196:embryology*; D051245:Retinal Bipolar Cells / Q000166:cytology*; D017948:Retinal Rod Photoreceptor Cells / Q000166:cytology*; D014157:Transcription Factors / Q000502:physiology
chemical_list: D018398:Homeodomain Proteins; C497762:Notch1 protein, mouse; D057095:Nuclear Receptor Subfamily 1, Group F, Member 2; D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse; C513258:Prdm1 protein, mouse; D051881:Receptor, Notch1; C539741:Rorb protein, mouse; D014157:Transcription Factors; C088975:Vsx2 protein, mouse; D000074462:Positive Regulatory Domain I-Binding Factor 1