June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Prdm8 and Bhlhb4 in the retina and CNS
Author Affiliations & Notes
  • Sasha Woods
    Academic Unit of Ophthalmology, University of Bristol, Bristol, United Kingdom
  • Andrew Stewart
    School of Biosciences, Cardiff University, Cardiff, United Kingdom
  • Cynthia Jung
    Molecular Genetics, University of Toronto, Toronto, ON, Canada
  • Sarah Ross
    Department of Neurobiology, Harvard Medical School, Boston, MA
    Department of Neurobiology and Anesthesiology, University of Pittsburgh, Pittsburgh, PA
  • Andrew Dick
    Academic Unit of Ophthalmology, University of Bristol, Bristol, United Kingdom
  • Clea Warburton
    Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom
  • Roderick McInnes
    Molecular Genetics, University of Toronto, Toronto, ON, Canada
  • Denize Atan
    Academic Unit of Ophthalmology, University of Bristol, Bristol, United Kingdom
  • Footnotes
    Commercial Relationships Sasha Woods, None; Andrew Stewart, None; Cynthia Jung, None; Sarah Ross, None; Andrew Dick, Novartis (C), Novartis (F), GSK (F), Abbott (F); Clea Warburton, None; Roderick McInnes, None; Denize Atan, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 2478. doi:
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      Sasha Woods, Andrew Stewart, Cynthia Jung, Sarah Ross, Andrew Dick, Clea Warburton, Roderick McInnes, Denize Atan; Prdm8 and Bhlhb4 in the retina and CNS. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2478.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Understanding the genetic regulation of retinal development is key to advancing therapies for disease. Bhlhb4 is a transcription factor (TF) essential to the maturation of the major class of retinal interneurons, rod bipolar cells (RBs). Adult Bhlhb4-/- mice have b wave deficits on dark adapted ERGs, a defect of RB signalling that models the human disorder Congenital Stationary Night Blindness. RBs are born in normal numbers in Bhlhb4-/- retina but die from PN8, suggesting Bhlhb4 is required for RB survival. In the CNS, Bhlhb4 is expressed the developing forebrain and in adult cerebellum and hippocampus. We describe a second mouse model lacking the TF, Prdm8, that phenocopies the Bhlhb4-/- model. Both TFs regulate the final stages of RB development in the retina and have parallel functions in the regulation of interneuron development elsewhere in the CNS.

Methods: Prdm8 and Bhlhb4 expression in wildtype (wt) retina and CNS was analysed by immunofluorescence using cell specific markers. Retinal transcriptomes of Prdm8-/-, Bhlhb4-/- and wt mice at PN6 were compared using Affymetrix Murine Genome 430 2.0 arrays with a false discovery rate (FDR) of up to 10%. Differential gene expression between mutant and littermatched wt retina was quantified by rtPCR. Morphological differences between mutant and wt brains were analysed by MRI; and neurobehavioural phenotypes with SHIRPA screening tests and the Morris water maze.

Results: Adult Prdm8-/- and Bhlhb4-/- retinas lack RBs and demonstrate b wave deficits on dark adapted ERGs, consistent with compromised RB circuitry. In both models, RBs are born in normal numbers but die apoptotically from PN8. Prdm8 and Bhlhb4 are co-expressed in RBs at PN5 to PN12 and from PN14 to adulthood. At PN6, Bhlhb4 is downregulated in Prdm8-/- retina (p=0.003) whilst Prdm8 expression is unchanged in Bhlhb4-/- retina (p=0.5). Non-overlapping genes are differentially expressed in Prdm8-/- and Bhlhb4-/- retina at PN6. In the latter, the most significantly downregulated genes, c-Rel and Neu3 (FDR=0%), are implicated in apoptosis. In the CNS, Prdm8 and Bhlhb4 are coexpressed in adult cerebellum and hippocampus. Prdm8-/- mice demonstrate neurobehavioural deficits and MRI changes consistent with impaired hippocampal and cerebellar development that overlap with deficits in Bhlhb4-/- mice.

Conclusions: We propose a model in which Prdm8 and Bhlhb4 coordinately regulate the development of specific interneuron subtypes in retina and brain.

Keywords: 435 bipolar cells • 497 development • 739 transcription factors  
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