title: Transcription factor PRDM8 is required for rod bipolar and type 2 OFF-cone bipolar cell survival and amacrine subtype identity.
abstract: Retinal bipolar (BP) cells mediate the earliest steps in image processing in the visual system, but the genetic pathways that regulate their development and function are incompletely known. We identified PRDI-BF1 and RIZ homology domain containing 8 (PRDM8) as a highly conserved transcription factor that is abundantly expressed in mouse retina. During development and in maturity, PRDM8 is expressed strongly in BP cells and a fraction of amacrine and ganglion cells. To determine whether Prdm8 is essential to BP cell development or physiology, we targeted the gene in mice. Prdm8(EGFP/EGFP) mice showed nonprogressive b-wave deficits on electroretinograms, consistent with compromised BP cell function or circuitry resembling the incomplete form of human congenital stationary night blindness (CSNB). BP cell specification was normal in Prdm8(EGFP/EGFP) retina as determined by VSX2(+) cell numbers and retinal morphology at postnatal day 6. BP subtype differentiation was impaired, however, as indicated by absent or diminished expression of BP subtype-specific markers, including the putative PRDM8 regulatory target PKCα (Prkca) and its protein. By adulthood, rod bipolar (RB) and type 2 OFF-cone bipolar (CB) cells were nearly absent from Prdm8-null mice. Although no change was detected in total amacrine cell (AC) numbers, increased PRKCA(+) and cholinergic ACs and decreased GABAergic ACs were seen, suggesting an alteration in amacrine subtype identity. These findings establish that PRDM8 is required for RB and type 2 OFF-CB cell survival and amacrine subtype identity, and they present PRDM8 as a candidate gene for human CSNB.
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5G 1X8; Program in Developmental Biology, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8;
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Jung
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5G 1X8; Program in Developmental Biology, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8; Academic Department of Ophthalmology, School of Clinical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom;
authors.forename: Denize
authors.initials: D
authors.lastname: Atan
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5G 1X8; Program in Developmental Biology, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8;
authors.forename: David
authors.initials: D
authors.lastname: Ng
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5G 1X8; Program in Developmental Biology, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8;
authors.forename: Lynda
authors.initials: L
authors.lastname: Ploder
authors.affiliation: Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15213; Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA 15213; Center for Pain Research, University of Pittsburgh, Pittsburgh, PA 15213;
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Ross
authors.affiliation: Retina Foundation of the Southwest, Dallas, TX 75231;
authors.forename: Martin
authors.initials: M
authors.lastname: Klein
authors.affiliation: Retina Foundation of the Southwest, Dallas, TX 75231;
authors.forename: David G
authors.initials: DG
authors.lastname: Birch
authors.affiliation: Lady Davis Research Institute, Jewish General Hospital, Montreal, QC, Canada H3T 1E2;
authors.forename: Eduardo
authors.initials: E
authors.lastname: Diez
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5G 1X8; Program in Developmental Biology, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8; Lady Davis Research Institute, Jewish General Hospital, Montreal, QC, Canada H3T 1E2; Department of Human Genetics, McGill University, Montreal, QC, Canada H3A 1B1; Department of Biochemistry, McGill University, Montreal, QC, Canada H3G 1Y6 rod.mcinnes@mcgill.ca.
authors.forename: Roderick R
authors.initials: RR
authors.lastname: McInnes
mesh_terms: D025042:Amacrine Cells / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D002470:Cell Survival / Q000502:physiology*; D004268:DNA-Binding Proteins; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D051245:Retinal Bipolar Cells / Q000166:cytology* / Q000378:metabolism; D017949:Retinal Cone Photoreceptor Cells / Q000166:cytology / Q000378:metabolism; D017948:Retinal Rod Photoreceptor Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D000076983:Histone Methyltransferases; C543643:PRDM8 protein, mouse; D011495:Histone-Lysine N-Methyltransferase
keywords: amacrine cell; bipolar cell; development; genetics; retina