December 2013
Volume 13, Issue 15
Free
OSA Fall Vision Meeting Abstract  |   October 2013
Hes1 promotes additional cell cycles when used to replace Math5
Author Affiliations
  • Steven Wang
    Department of Ophthalmology and Visual Science, University of Texas Medical School at Houston, Houston, Texas USA
  • Rui Chen
    Human Genome Center, Baylor College of Medicine, Houston, Texas, USA
  • Takae Kiyama
    Department of Ophthalmology and Visual Science, University of Texas Medical School at Houston, Houston, Texas USA
Journal of Vision October 2013, Vol.13, P1. doi:10.1167/13.15.36
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      Steven Wang, Rui Chen, Takae Kiyama; Hes1 promotes additional cell cycles when used to replace Math5. Journal of Vision 2013;13(15):P1. doi: 10.1167/13.15.36.

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

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Abstract

The proneural factor Math5 is required for cell cycle exit and essential for retinal ganglion cell (RGC) formation. Oppositely, the inhibitor type bHLH factor Hes1 prevents neurogenesis. During neurogenesis, Hes1 is repeatedly recruited for adding cell numbers. We hypothesize that replacing Math5 with Hes1 will lead to cell cycle reentry in retinal precursor cells, and that reactivation of Math5 after Hes1's ectopic action will restore RGCs in the retina. A Math5Hes1/Hes1 mouse line carrying a genetic element of loxP-Hes1-IRES-dsRed-loxP in place of Math5 coding sequence was generated. Hes1 excision would allow a Math5-IRES-hrGFPII cassette to resume Math5's position. Retinas at different stages were analyzed using proliferation markers. RNA-sequencing and qRT-PCR were performed to access molecular shifts. The Math5Hes1/Hes1 retinas showed 50% more proliferating cells then the wildtype retinas. The high proliferation rate resulted a bigger retina, which subsequently became thinner. Results of RNA-sequencing and qRT-PCR showed that neurogenic genes were downregulated and cell cycle promoting genes were upregulated. Elevated metabolic factors implied proliferating cells cells are deprived of energy. A Math5Hes1/Hes1;CreERTM line was generated and Tamoxifen was administered to reactivate Math5. Math5 reactivation resulted in massive RGC restoration, but some axons appeared to be misrouted. Results conclude that additional cell cycles can be coerced in retinal precursors by replacing Math5 with Hes1. However, over-proliferated cells cannot survive in such an aberrant retinal environment in which most cells stall in an undifferentiated, or “confused,” state. Reactivation of Math5 can restore RGC production in vivo.

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