Date of Award
Doctor of Philosophy (PhD)
Development of retinal structure and function requires precisely controlled gene expression. This process is regulated by both cell type-specific transcription factors and general epigenetic regulators including enzymes that modify histones. The MLL family of histone methyltransferases catalyze histone H3 lysine 4 di-and tri-methylation that are often associated with gene activation. Its members MLL1, MLL2 and MLL3 are essential for development, while MLL1 in particular is required for neurogenesis in the postnatal mouse brain. All three Mlls are expressed in the developing and mature mouse retinas. We thus hypothesize that these MLL family members play essential roles in development and maintenance of retinal structure and function.
To test this hypothesis we created mice deficient in Mll1, Mll2 or Mll3 in the developing retina and in differentiated photoreceptors. Though loss of Mll1 in differentiated rods and cones had no detectable morphological or functional changes, Mll1 deficiency in early retinal progenitor cells resulted in severely impaired retinal function and thinner retinas. The thinning of these retinas was due to proliferative and cell cycle defects. In addition, these retinas had increased proportion of Muller glia cells from late-born cells, suggesting that MLL1 promotes neurogenesis above gliogenesis. Deficiency of Mll1 in the developing retina also resulted in the loss of horizontal cells between postnatal day 7 (P7) and P14 and abnormal synapses between photoreceptors and inner neurons. These studies reveal that while MLL1 plays a limited role in retinal maintenance; it is required for the retinal developmental program controlling progenitor cell proliferation, cell-fate specification, and terminal differentiation. In contrast, the results of Mll2 and Mll3 deficiency suggest that MLL2 also plays a role, though not as important as MLL1, in retinal development, while MLL3 is dispensable. More importantly, deleting both Mll1 and Mll2 produced highly disrupted retinal structure and function that are more severe than with loss of Mll1 or Mll2 alone. This genetic “interaction” is highly specific, as it does not occur between Mll1 and Mll3. Together, our results suggest that MLL1 and MLL2 play overlapping and distinct roles in developing appropriate retinal structure and function. Future studies are underway to decipher the underlying molecular mechanisms.
Chair and Committee
Joseph Corbo, Daniel Kerschensteiner, Kristen Kroll, Joshua Rubin
Brightman, Diana Schorry, "The MLL Family of Histone Methyltransferases Plays Important Roles in Retinal Development" (2015). Arts & Sciences Electronic Theses and Dissertations. 638.
Available for download on Thursday, August 15, 2115