June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
The MLL1 Histone Methyltransferease is Essential for Development of Photoreceptor Function
Author Affiliations & Notes
  • Diana Brightman
    Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, MO
  • Ray Suzuki
    Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, MO
  • Shiming Chen
    Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, MO
  • Footnotes
    Commercial Relationships Diana Brightman, None; Ray Suzuki, None; Shiming Chen, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 2617. doi:https://doi.org/
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    • Get Citation

      Diana Brightman, Ray Suzuki, Shiming Chen; The MLL1 Histone Methyltransferease is Essential for Development of Photoreceptor Function. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2617. doi: https://doi.org/.

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

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Abstract

Purpose: Development and maintenance of retinal photoreceptor function requires precisely controlled gene expression. This is regulated by both photoreceptor-specific and general transcription regulators, including histone modification enzymes. Members of the MLL family of histone H3K4 methyltransferases are expressed in mouse photoreceptors. The most prominent of these is MLL1 whose expression increases between postnatal day 2 (P2) and P14, a critical period for photoreceptor terminal differentiation. MLL1 expression depends on the key photoreceptor-specific transcription factor CRX, suggesting a potential role of MLL1 in the CRX regulatory pathway. We determined the role of MLL1 in photoreceptor gene expression, development and survival using a loss-of-function approach.

Methods: To avoid embryonic lethality, Cre-loxP-mediated conditional knockout (CKO) was used. Mice with Mll1 floxed alleles (Mll1fl/fl) were crossed with Crx-Cre mice to create Mll1 CKO in the developing retina. Mll1 CKO mice show morphological changes in the retina by H&E staining, immunohistochemistry (IHC) and electron microscopy (EM), and visual function changes by electroretinogram (ERG).

Results: Cre activity was found in all cell layers of the developing Mll1 CKO retina, in a superior-to-inferior gradient. As a result, Mll1 expression was uniformly depleted in the superior region, where all retinal layers were significantly thinner by morphometry. IHC and EM analyses show abnormal superior outer plexiform layer (OPL) synapses. The intensity of the presynaptic markers V-GLUT1 and CTBP2 were markedly decreased at the OPL. Calbindin-positive horizontal cells were also reduced, indicative of postsynaptic defects. Consistent with these defects, both dark and light-adapted ERGs of 1-month-old Mll1 CKO mice were significantly decreased, suggesting defects in rod, cone, and inner retina functions. The morphological and functional changes are stable to 6 months of age, suggesting a developmental origin, not degeneration.

Conclusions: MLL1 is required for the development of appropriate retinal structure and function. Additional Mll1 CKO using photoreceptor and INL cell-type-specific Cre lines are in progress to determine cell autonomy and underlying molecular mechanisms. These studies will shed light on how general epigenetic modulators contribute to the regulation of cell-type specific gene expression and development.

Keywords: 533 gene/expression • 698 retinal development • 738 transcription  
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