Transcription factor PRDM8 is required for rod bipolar and type 2 OFF-cone bipolar cell survival and amacrine subtype identity

Cynthia C. Jung, Denize Atan, David Ng, Lynda Ploder, Sarah E. Ross, Martin Klein, David G. Birch, Eduardo Diez, and Roderick R. McInnes
PNAS June 9, 2015 112 (23) E3010-E3019; first published May 28, 2015 https://doi.org/10.1073/pnas.1505870112

  1. Edited by Jeremy Nathans, Johns Hopkins University, Baltimore, MD, and approved May 1, 2015 (received for review March 26, 2015)

Significance

Knowledge of the molecules that guide retinal interneuron formation is incomplete. We showed that PRDI-BF1 and RIZ homology domain containing 8 (PRDM8) is required for the development of rod bipolar cells and OFF-cone bipolar subtypes as well as amacrine cell identity. Although bipolar cells were specified in Prdm8-null mice, rod bipolar cell differentiation was impaired, leading to their death and near absence from adult retina. This defect disrupts postphotoreceptor signal transduction, as shown by nonprogressive b-wave deficits in electroretinograms. Our findings suggest PRDM8 as a candidate gene for human congenital stationary night blindness. They also establish PRDM8 as a component of the regulatory network governing bipolar cell development and amacrine cell diversity, aiding efforts to generate these essential interneurons in vitro.

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. Prdm8EGFP/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 Prdm8EGFP/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.

Footnotes

  • ↵1C.C.J. and D.A. contributed equally to this work.

  • ↵2To whom correspondence should be addressed. Email: rod.mcinnes{at}mcgill.ca.

  • Author contributions: C.C.J., D.A., D.G.B., and R.R.M. designed research; C.C.J., D.A., D.N., and M.K. performed research; C.C.J., D.A., L.P., S.E.R., and D.G.B. contributed new reagents/analytic tools; C.C.J., D.A., M.K., D.G.B., and R.R.M. analyzed data; and C.C.J., D.A., E.D., and R.R.M. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1505870112/-/DCSupplemental.

  1. Cynthia C. Junga,b,1,
  2. Denize Atana,b,c,1,
  3. David Nga,b,
  4. Lynda Plodera,b,
  5. Sarah E. Rossd,e,f,
  6. Martin Kleing,
  7. David G. Birchg,
  8. Eduardo Diezh, and
  9. Roderick R. McInnesa,b,h,i,j,2
  1. aDepartment of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5G 1X8;
  2. bProgram in Developmental Biology, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8;
  3. cAcademic Department of Ophthalmology, School of Clinical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom;
  4. dDepartment of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15213;
  5. eDepartment of Anesthesiology, University of Pittsburgh, Pittsburgh, PA 15213;
  6. fCenter for Pain Research, University of Pittsburgh, Pittsburgh, PA 15213;
  7. gRetina Foundation of the Southwest, Dallas, TX 75231;
  8. hLady Davis Research Institute, Jewish General Hospital, Montreal, QC, Canada H3T 1E2;
  9. iDepartment of Human Genetics, McGill University, Montreal, QC, Canada H3A 1B1;
  10. jDepartment of Biochemistry, McGill University, Montreal, QC, Canada H3G 1Y6

  1. Edited by Jeremy Nathans, Johns Hopkins University, Baltimore, MD, and approved May 1, 2015 (received for review March 26, 2015)

Significance

Knowledge of the molecules that guide retinal interneuron formation is incomplete. We showed that PRDI-BF1 and RIZ homology domain containing 8 (PRDM8) is required for the development of rod bipolar cells and OFF-cone bipolar subtypes as well as amacrine cell identity. Although bipolar cells were specified in Prdm8-null mice, rod bipolar cell differentiation was impaired, leading to their death and near absence from adult retina. This defect disrupts postphotoreceptor signal transduction, as shown by nonprogressive b-wave deficits in electroretinograms. Our findings suggest PRDM8 as a candidate gene for human congenital stationary night blindness. They also establish PRDM8 as a component of the regulatory network governing bipolar cell development and amacrine cell diversity, aiding efforts to generate these essential interneurons in vitro.

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. Prdm8EGFP/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 Prdm8EGFP/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.

  • retina
  • bipolar cell
  • amacrine cell
  • genetics
  • development

Footnotes

  • ↵1C.C.J. and D.A. contributed equally to this work.

  • ↵2To whom correspondence should be addressed. Email: rod.mcinnes{at}mcgill.ca.

  • Author contributions: C.C.J., D.A., D.G.B., and R.R.M. designed research; C.C.J., D.A., D.N., and M.K. performed research; C.C.J., D.A., L.P., S.E.R., and D.G.B. contributed new reagents/analytic tools; C.C.J., D.A., M.K., D.G.B., and R.R.M. analyzed data; and C.C.J., D.A., E.D., and R.R.M. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1505870112/-/DCSupplemental.

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Role of PRDM8 in retinal development
Cynthia C. Jung, Denize Atan, David Ng, Lynda Ploder, Sarah E. Ross, Martin Klein, David G. Birch, Eduardo Diez, Roderick R. McInnes
Proceedings of the National Academy of Sciences Jun 2015, 112 (23) E3010-E3019; DOI: 10.1073/pnas.1505870112
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