您当前的位置: 首页 > 网页快照
mTORC1-induced retinal progenitor cell overproliferation leads to accelerated mitotic aging and degeneration of descendent Müller glia
Article . Figures and data . Abstract . Data availability . Article and author information . Metrics . Abstract . Retinal progenitor cells (RPCs) divide in limited numbers to generate the cells comprising vertebrate retina. The molecular mechanism that leads RPC to the division limit, however, remains elusive. Here, we find that the hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) in an RPC subset by deletion of tuberous sclerosis complex 1 ( Tsc1 ) makes the RPCs arrive at the division limit precociously and produce Müller glia (MG) that degenerate from senescence-associated cell death. We further show the hyperproliferation of Tsc1 -deficient RPCs and the degeneration of MG in the mouse retina disappear by concomitant deletion of hypoxia-induced factor 1- a ( Hif1 a ), which induces glycolytic gene expression to support mTORC1-induced RPC proliferation. Collectively, our results suggest that, by having mTORC1 constitutively active, an RPC divides and exhausts mitotic capacity faster than neighboring RPCs, and thus produces retinal cells that degenerate with aging-related changes. Add a comment + Open annotations. The current annotation count on this page is being calculated . Data availability . All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1 and 2. Article and author information . Author details . Soyeon Lim . Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea Competing interests . The authors declare that no competing interests exist. You-Joung Kim . Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea Competing interests . The authors declare that no competing interests exist. Sooyeon Park . Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea Competing interests . The authors declare that no competing interests exist. Ji-heon Choi . Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea Competing interests . The authors declare that no competing interests exist. "This ORCID iD identifies the author of this article:" 0000-0001-9204-1755 Younghoon Sung . Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea Competing interests . The authors declare that no competing interests exist. Katsuhiko Nishimori . Obesity and Internal Inflammation; Bioregulation and Pharmacological Medicine, Fukushima Medical University, Fukushima, Japan Competing interests . The authors declare that no competing interests exist. Zybmek Kozmik . Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic Competing interests . The authors declare that no competing interests exist. Han-Woong Lee . Biochemistry, Yonsei University, Seoul, Republic of Korea Competing interests . The authors declare that no competing interests exist. "This ORCID iD identifies the author of this article:" 0000-0001-9515-3605 Jin Woo Kim . Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea For correspondence . jinwookim@kaist.ac.kr Competing interests . The authors declare that no competing interests exist. "This ORCID iD identifies the author of this article:" 0000-0003-0767-1918 Funding . National Research Foundation of Korea (2017R1A2B3002862) . Jin Woo Kim . National Research Foundation of Korea (2018R1A5A1024261) . Jin Woo Kim . Samsung Science and Technology Foundation (SSTF-BA1802-10) . Jin Woo Kim . The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Ethics . Animal experimentation: Experiments using the mice were carried out according to the guidance of Institutional Animal Care and Use Committee (IACUC) of KAIST (KA-2014-20). Reviewing Editor . Paola Bovolenta, CSIC-UAM, Spain . Publication history . Received: May 5, 2021 . Accepted: October 17, 2021 . Accepted Manuscript published: October 22, 2021 (version 1) . Copyright . ? 2021, Lim et al. This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited. Metrics . 19 Page views . 1 Downloads . 0 Citations . Article citation count generated by polling the highest count across the following sources: Crossref , PubMed Central , Scopus . Download links . A two-part list of links to download the article, or parts of the article, in various formats. Downloads (link to download the article as PDF) . Article PDF . Download citations (links to download the citations from this article in formats compatible with various reference manager tools) . BibTeX . RIS . Open citations (links to open the citations from this article in various online reference manager services) . Mendeley . ReadCube . Categories and tags . Research Article . Developmental Biology . Research organism . Mouse . Of interest . Adult stem cells and niche cells segregate gradually from common precursors that build the adult Drosophila ovary during pupal development . Amy Reilein et al. Research Article Updated Oct 22, 2021 Further reading . Further reading . Developmental Biology . Stem Cells and Regenerative Medicine . Adult stem cells and niche cells segregate gradually from common precursors that build the adult Drosophila ovary during pupal development . Amy Reilein et al. Research Article Updated Oct 22, 2021 Production of proliferative follicle cells (FCs) and quiescent escort cells (ECs) by follicle stem cells (FSCs) in adult Drosophila ovaries is regulated by niche signals from anterior (cap cells, ECs) and posterior (polar FCs) sources. Here we show that ECs, FSCs, and FCs develop from common pupal precursors, with different fates acquired by progressive separation of cells along the AP axis and a graded decline in anterior cell proliferation. ECs, FSCs, and most FCs derive from intermingled cell (IC) precursors interspersed with germline cells. Precursors also accumulate posterior to ICs before engulfing a naked germline cyst projected out of the germarium to form the first egg chamber and posterior polar FC signaling center. Thus, stem and niche cells develop in appropriate numbers and spatial organization through regulated proliferative expansion together with progressive establishment of spatial signaling cues that guide adult cell behavior, rather than through rigid early specification events. Developmental Biology . Neuroscience . Stretching of the retinal pigment epithelium contributes to zebrafish optic cup morphogenesis . Tania Moreno-Mármol et al. Research Article Updated Oct 21, 2021 The vertebrate eye primordium consists of a pseudostratified neuroepithelium, the optic vesicle (OV), in which cells acquire neural retina or retinal pigment epithelium (RPE) fates. As these fates arise, the OV assumes a cup shape, influenced by mechanical forces generated within the neural retina. Whether the RPE passively adapts to retinal changes or actively contributes to OV morphogenesis remains unexplored. We generated a zebrafish Tg(E1- bhlhe40 :GFP) line to track RPE morphogenesis and interrogate its participation in OV folding. We show that, in virtual absence of proliferation, RPE cells stretch and flatten, thereby matching the retinal curvature and promoting OV folding. Localized interference with the RPE cytoskeleton disrupts tissue stretching and OV folding. Thus, extreme RPE flattening and accelerated differentiation are efficient solutions adopted by fast-developing species to enable timely optic cup formation. This mechanism differs in amniotes, in which proliferation drives RPE expansion with a much-reduced need of cell flattening. Developmental Biology . Stem Cells and Regenerative Medicine . Retinoic acid signaling is directly activated in cardiomyocytes and protects mouse hearts from apoptosis after myocardial infarction . Fabio Da Silva et al. Research Article Updated Oct 21, 2021 Retinoic acid (RA) is an essential signaling molecule for cardiac development and plays a protective role in the heart after myocardial infarction (MI). In both cases, the effect of RA signaling on cardiomyocytes, the principle cell type of the heart, has been reported to be indirect. Here we have developed an inducible murine transgenic RA-reporter line using CreER T2 technology that permits lineage tracing of RA-responsive cells and faithfully recapitulates endogenous RA activity in multiple organs during embryonic development. Strikingly, we have observed a direct RA response in cardiomyocytes during mid-late gestation and after MI. Ablation of RA signaling through deletion of the Aldh1a1/a2/a3 genes encoding RA-synthesizing enzymes leads to increased cardiomyocyte apoptosis in adults subjected to MI. RNA sequencing analysis reveals Tgm2 and Ace1, two genes with well-established links to cardiac repair , as potential targets of RA signaling in primary cardiomyocytes, thereby providing novel links between the RA pathway and heart disease. .
From:
系统抽取主题     
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)  
(1)