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miR Cluster 143/145 Directly Targets Nrl and Regulates Rod Photoreceptor Development

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Abstract

Retinal histogenesis requires coordinated and temporal functioning of factors by which different cell types are generated from multipotent progenitors. Development of rod photoreceptors is regulated by multiple transcription factors, and Nrl is one of the major factors involved in their fate specification. Presence or absence of Nrl at the postnatal stages decides the generation of cone photoreceptors or other later retinal cells. This suggests the need for regulated expression of Nrl in order to accelerate the generation of other cell types during retinal development. We found that miR cluster 143/145, comprising miR-143 and miR-145, targets and imparts a posttranscriptional inhibition of Nrl. Expression of both miRNAs was differentially regulated during retinal development and showed least expression at PN1 stage in which most of the rod photoreceptors are generated. Downregulation of rod photoreceptor regulators and markers upon miR cluster 143/145 overexpression demonstrated that this cluster indeed negatively regulates rod photoreceptors. Further, we prove that Nrl positively regulates miR cluster 143/145, thus establishing a feedback loop regulatory mechanism. This may be one possible mechanism by which Nrl is posttranscriptionally regulated to facilitate the generation of other cell types in retina.

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Acknowledgments

We would like to thank Dr. Ruby John Anto, Scientist F, and Dr. Jackson James, Scientist EII, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India for helping us with EMSA experiments and critical evaluation of the manuscript, respectively. We extend our gratitude towards Dr. Anand Swaroop, NEI, MD, USA for Nrl expression vectors, and Dr. Beena Pillai, IGIB, New Delhi for pRIPM, pSilencer, and pSicheck2 vectors. We also thank Prof. Kageyama, Kyoto University, Japan for d2EGFP construct.

Author Contributions

S.S. performed the miR and target interaction, miR perturbation, and Western blot experiments; V.A.R. was involved in cloning the pre-miR and 3′UTR sequences and ex vivo experiments; L.S. performed RT-PCR experiments; J.A and M.S. carried out EMSA experiments; K.C.S. did the bioinformatic analysis; and A.V.D. conceived the idea, designed the experiments, and prepared the manuscript.

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  1. Ani V Das

    Present address: Cancer Research Program-9, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, 695014, Kerala, India

Authors and Affiliations

  1. Molecular Neurobiology Laboratory, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, 695014, Kerala, India

    Sreekumaran Sreekanth & Ani V Das

  2. Neuro Stem Cell Biology Laboratory, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, 695014, Kerala, India

    Vazhanthodi A Rasheed & Lalitha Soundararajan

  3. Cancer Research Program-2, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, 695014, Kerala, India

    Jayesh Antony & Minakshi Saikia

  4. Bioinformatic Facility, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, 695014, Kerala, India

    Krishnankutty Chandrika Sivakumar

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This work was supported by funding from the Department of Science & Technology, Government of India and intramural funding from Rajiv Gandhi Centre for Biotechnology, Kerala, India.

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Sreekanth, S., Rasheed, V.A., Soundararajan, L. et al. miR Cluster 143/145 Directly Targets Nrl and Regulates Rod Photoreceptor Development. Mol Neurobiol 54, 8033–8049 (2017). https://doi.org/10.1007/s12035-016-0237-0

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