RONIN Is an Essential Transcriptional Regulator of Genes Required for Mitochondrial Function in the Developing Retina

• Published in: Cell reports (Cambridge) Vol. 14; no. 7; pp. 1684 - 1697
• Main Authors: Poché, Ross A., Zhang, Min, Rueda, Elda M., Tong, Xuefei, McElwee, Melissa L., Wong, Leeyean, Hsu, Chih-Wei, Dejosez, Marion, Burns, Alan R., Fox, Donald A., Martin, James F., Zwaka, Thomas P., Dickinson, Mary E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23-02-2016
• Subjects: Adenosine Triphosphate - biosynthesis; Animals; Cell Differentiation; Cell Proliferation; Electron Transport Chain Complex Proteins - genetics; Electron Transport Chain Complex Proteins - metabolism; Embryo, Mammalian; G1 Phase Cell Cycle Checkpoints - genetics; Gene Expression Regulation, Developmental; Mice; Mice, Transgenic; Mitochondria - metabolism; Oxidative Stress; Photoreceptor Cells, Vertebrate - cytology; Photoreceptor Cells, Vertebrate - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; Signal Transduction; Stem Cells - cytology; Stem Cells - metabolism; Transcription, Genetic
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.01.039

A fundamental principle governing organ size and function is the fine balance between cell proliferation and cell differentiation. Here, we identify RONIN (THAP11) as a key transcriptional regulator of retinal progenitor cell (RPC) proliferation. RPC-specific loss of Ronin results in a phenotype strikingly similar to that resulting from the G1- to S-phase arrest and photoreceptor degeneration observed in the Cyclin D1 null mutants. However, we determined that, rather than regulating canonical cell-cycle genes, RONIN regulates a cohort of mitochondrial genes including components of the electron transport chain (ETC), which have been recently implicated as direct regulators of the cell cycle. Coincidentally, with premature cell-cycle exit, Ronin mutants exhibited deficient ETC activity, reduced ATP levels, and increased oxidative stress that we ascribe to specific loss of subunits within complexes I, III, and IV. These data implicate RONIN as a positive regulator of mitochondrial gene expression that coordinates mitochondrial activity and cell-cycle progression.
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•Ronin loss causes retinal progenitor cell-cycle arrest and photoreceptor degeneration•Striking phenocopy of Cyclin D1 nulls, but RONIN functions independently•RONIN is a regulator of mitochondrial gene expression including ETC components•RONIN coordinates mitochondrial activity and neural progenitor proliferation
Poché et al. identify Ronin (Thap11) as an important regulator of mitochondrial gene expression that coordinates mitochondrial activity and cell-cycle progression. Loss of Ronin function leads to specific deficits in the electron transport chain as well as premature cell-cycle exit, excessive neurogenesis, and cell death.