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Xiuqian Mu, Fuguo Wu, Tadeusz J Kaczynski, Martin Turner, Tao Liu; Regulation of mRNA decay by Zfp36l1 and Zfp36l2 in retinal development and maintenance. Invest. Ophthalmol. Vis. Sci. 2019;60(9):6025.
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Little is known about how post-transcriptional regulation impacts retinal development and maintenance. We tried to address this issue by studying two members of the TTP (tristetraprolin) mRNA binding protein family, Zfp36l1 and Zfp36l2. This family of CCCH zinc finger proteins are highly conserved through evolution and are involved in diverse biological processes. They carry out their functions by binding to the AU-rich elements (AREs) in the 3’ UTR of target mRNAs to promote their decay. Our purpose was to examine their roles in retinal development and maintenance by conditionally deleting their genes and analyzing the morphological and molecular changes.
First, we examined the expression patterns of Zfp36l1 and Zfp36l2 throughout retinal development by in situ hybridization. Next, using floxed Zfp36l1 and Zfp36l2 alleles, together with the Chx10-Cre line, we generated conditional single and double knockout mice. We then analyzed their retinas by histology, immunofluorescence staining, BrdU labeling, and RNA-seq.
By in situ hybridization and immunofluorescence staining, we found that Zfp36l1 and Zfp36l2 were expressed in retinal progenitor cells during development, and Müller glial cells and photoreceptors in the mature retina. Our analysis of the mutant retinas showed that, whereas the single knockout retinas appeared largely normal, the double knockout retina did not develop normally and degenerated rapidly after development completed. RNA-seq analysis indicated that Zfp36l1 and Zfp36l2 interacted with multiple signaling pathways to impact the balance between proliferation and differentiation. Our current efforts are aimed to delineate their distinct roles in retinal development and maintenance and to identify their direct targets in both stages.
Our results suggest that regulation of mRNA decay plays critical roles in the retina and that Zfp36l1 and Zfp36l2 are critical regulators of mRNA decay functioning redundantly in both retinal development and maintenance. The discoveries we make add a new dimension to our knowledge of gene regulation in the retina.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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