mTORC1-induced retinal progenitor cell overproliferation leads to accelerated mitotic aging and degeneration of descendent Müller glia

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...

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Autores principales:	Soyeon Lim, You-Joung Kim, Sooyeon Park, Ji-heon Choi, Young Hoon Sung, Katsuhiko Nishimori, Zbynek Kozmik, Han-Woong Lee, Jin Woo Kim
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	retinal progenitor cell mitotic division limit clonal expansion mTORC1 Hif1a glycolysis Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/a03459b91f7d4c9f9755e27b55ef3cbb
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spelling	oai:doaj.org-article:a03459b91f7d4c9f9755e27b55ef3cbb2021-11-09T09:09:47ZmTORC1-induced retinal progenitor cell overproliferation leads to accelerated mitotic aging and degeneration of descendent Müller glia10.7554/eLife.700792050-084Xe70079https://doaj.org/article/a03459b91f7d4c9f9755e27b55ef3cbb2021-10-01T00:00:00Zhttps://elifesciences.org/articles/70079https://doaj.org/toc/2050-084XRetinal 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-alpha (Hif1a), 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.Soyeon LimYou-Joung KimSooyeon ParkJi-heon ChoiYoung Hoon SungKatsuhiko NishimoriZbynek KozmikHan-Woong LeeJin Woo KimeLife Sciences Publications Ltdarticleretinal progenitor cellmitotic division limitclonal expansion mTORC1Hif1aglycolysisMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	retinal progenitor cell mitotic division limit clonal expansion mTORC1 Hif1a glycolysis Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	retinal progenitor cell mitotic division limit clonal expansion mTORC1 Hif1a glycolysis Medicine R Science Q Biology (General) QH301-705.5 Soyeon Lim You-Joung Kim Sooyeon Park Ji-heon Choi Young Hoon Sung Katsuhiko Nishimori Zbynek Kozmik Han-Woong Lee Jin Woo Kim mTORC1-induced retinal progenitor cell overproliferation leads to accelerated mitotic aging and degeneration of descendent Müller glia
description	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-alpha (Hif1a), 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.
format	article
author	Soyeon Lim You-Joung Kim Sooyeon Park Ji-heon Choi Young Hoon Sung Katsuhiko Nishimori Zbynek Kozmik Han-Woong Lee Jin Woo Kim
author_facet	Soyeon Lim You-Joung Kim Sooyeon Park Ji-heon Choi Young Hoon Sung Katsuhiko Nishimori Zbynek Kozmik Han-Woong Lee Jin Woo Kim
author_sort	Soyeon Lim
title	mTORC1-induced retinal progenitor cell overproliferation leads to accelerated mitotic aging and degeneration of descendent Müller glia
title_short	mTORC1-induced retinal progenitor cell overproliferation leads to accelerated mitotic aging and degeneration of descendent Müller glia
title_full	mTORC1-induced retinal progenitor cell overproliferation leads to accelerated mitotic aging and degeneration of descendent Müller glia
title_fullStr	mTORC1-induced retinal progenitor cell overproliferation leads to accelerated mitotic aging and degeneration of descendent Müller glia
title_full_unstemmed	mTORC1-induced retinal progenitor cell overproliferation leads to accelerated mitotic aging and degeneration of descendent Müller glia
title_sort	mtorc1-induced retinal progenitor cell overproliferation leads to accelerated mitotic aging and degeneration of descendent müller glia
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/a03459b91f7d4c9f9755e27b55ef3cbb
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mTORC1-induced retinal progenitor cell overproliferation leads to accelerated mitotic aging and degeneration of descendent Müller glia

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