@article{7e6d2589a7194cb3822dc671ae7f2230,
title = "A Dedicated Evolutionarily Conserved Molecular Network Licenses Differentiated Cells to Return to the Cell Cycle",
abstract = "Differentiated cells can re-enter the cell cycle to repair tissue damage via a series of discrete morphological and molecular stages coordinated by the cellular energetics regulator mTORC1. We previously proposed the term “paligenosis” to describe this conserved cellular regeneration program. Here, we detail a molecular network regulating mTORC1 during paligenosis in both mouse pancreatic acinar and gastric chief cells. DDIT4 initially suppresses mTORC1 to induce autodegradation of differentiated cell components and damaged organelles. Later in paligenosis, IFRD1 suppresses p53 accumulation. Ifrd1−/− cells do not complete paligenosis because persistent p53 prevents mTORC1 reactivation and cell proliferation. Ddit4−/− cells never suppress mTORC1 and bypass the IFRD1 checkpoint on proliferation. Previous reports and our current data implicate DDIT4/IFRD1 in governing paligenosis in multiple organs and species. Thus, we propose that an evolutionarily conserved, dedicated molecular network has evolved to allow differentiated cells to re-enter the cell cycle (i.e., undergo paligenosis) after tissue injury. Video Abstract: [Figure presented] During regeneration or tumorigenesis, differentiated cells use an evolutionarily conserved program (paligenosis) to reprogram their metabolism and readopt a progenitor state. Miao et al. identify dedicated paligenosis genes: DDIT4 suppresses mTORC1 to induce massive autophagy that dismantles differentiated cell architecture, then IFRD1 derepresses mTORC1, licensing the dedifferentiated cell to proliferate.",
keywords = "ADM, Drosophila, SPEM, Schizosaccharomyces pombe, acinar-ductal metaplasia, regeneration, spasmolytic polypeptide-expressing metaplasia",
author = "Miao, {Zhi Feng} and Lewis, {Mark A.} and Cho, {Charles J.} and Mahliyah Adkins-Threats and Dongkook Park and Brown, {Jeffrey W.} and Sun, {Jing Xu} and Burclaff, {Joseph R.} and Susan Kennedy and Jianyun Lu and Marcus Mahar and Ilja Vietor and Huber, {Lukas A.} and Davidson, {Nicholas O.} and Valeria Cavalli and Rubin, {Deborah C.} and Wang, {Zhen Ning} and Mills, {Jason C.}",
note = "Funding Information: We thank Quark Pharmaceuticals Inc for allowing the opportunity to use the Ddit4 tm1.1 (KOMP)Vlcg/J (Ddit4 −/− ) mice. We thank Dr. Elena Feinstein (Quark Pharmaceuticals, Inc) and Prof. Rubin Tuder (University of Colorado Denver) for providing the Ddit4 tm1.1 (KOMP)Vlcg/J (Ddit4 −/− ) mice. We thank Dr. Paul Taghert and Dr. Craig Micchelli for Drosophila food and reagents and for Drosophila, which were also obtained from the Bloomington Drosophila Stock Center (NIH P40OD018537). We are deeply grateful to Spencer G. Willet (Washington University in St Louis) for critically revising the manuscript and figures. We thank the lab of David Denardo for training and use of HALO software. We acknowledge the AITAC of the Washington University Digestive Disease Center ( DDRCC : P30 DK052574 ) and the NIH Shared Instrumentation Grant S10 RR0227552 (for NanoZoomer slide scanning). M.A.L. was funded by T32-DK077653 (NIH, NIDDK ) by the DeNardo Education & Research Foundation Grant and a supplement to R01-DK094989 (NIH NIDDK ); M.A.-T. by T32-DK077653 (NIH, NIDDK ) and R25-GM103757 ( NIGMS , NIH); J.W.B. by T32-DK007130 (NIH NIDDK ); C.J.C. by T32-CA009547 (NIH NCI ); J.B. by T32-GM007067 ( NIGMS , NIH) and the Philip and Sima Needleman Student Fellowship in Regenerative Medicine; N.O.D. by R01s HL38180 ( NIH NHBLI), DK112378 , and DK56260 (NIH NIDDK ); D.C.R. by R01-DK106382 (NIH NIDDK ); Z.N.-W. by National Key R&D Program of China (MOST- 2017YFC0908300 ), National Natural Science Foundation of China ( 81961128026 and U1908207 ), and Major Scientific and Technological Special Project of Liaoning Province of China ( 2019020176-JH1/103 ); and J.C.M. by DK094989 , DK105129 , and DK110406 , by the Alvin J. Siteman Cancer Center –Barnes Jewish Hospital Foundation Cancer Frontier Fund, NIH National Cancer Institute P30 CA091842 and R01 CA246208 , and the Barnard Trust . Funding Information: We thank Quark Pharmaceuticals Inc for allowing the opportunity to use the Ddit4tm1.1 (KOMP)Vlcg/J (Ddit4?/?) mice. We thank Dr. Elena Feinstein (Quark Pharmaceuticals, Inc) and Prof. Rubin Tuder (University of Colorado Denver) for providing the Ddit4tm1.1 (KOMP)Vlcg/J (Ddit4?/?) mice. We thank Dr. Paul Taghert and Dr. Craig Micchelli for Drosophila food and reagents and for Drosophila, which were also obtained from the Bloomington Drosophila Stock Center (NIH P40OD018537). We are deeply grateful to Spencer G. Willet (Washington University in St Louis) for critically revising the manuscript and figures. We thank the lab of David Denardo for training and use of HALO software. We acknowledge the AITAC of the Washington University Digestive Disease Center (DDRCC: P30 DK052574) and the NIH Shared Instrumentation Grant S10 RR0227552 (for NanoZoomer slide scanning). M.A.L. was funded by T32-DK077653 (NIH, NIDDK) by the DeNardo Education & Research Foundation Grant and a supplement to R01-DK094989 (NIH NIDDK); M.A.-T. by T32-DK077653 (NIH, NIDDK) and R25-GM103757 (NIGMS, NIH); J.W.B. by T32-DK007130 (NIH NIDDK); C.J.C. by T32-CA009547(NIH NCI); J.B. by T32-GM007067 (NIGMS, NIH) and the Philip and Sima Needleman Student Fellowship in Regenerative Medicine; N.O.D. by R01s HL38180 (NIH NHBLI), DK112378, and DK56260 (NIH NIDDK); D.C.R. by R01-DK106382 (NIH NIDDK); Z.N.-W. by National Key R&D Program of China (MOST-2017YFC0908300), National Natural Science Foundation of China (81961128026 and U1908207), and Major Scientific and Technological Special Project of Liaoning Province of China (2019020176-JH1/103); and J.C.M. by DK094989, DK105129, and DK110406, by the Alvin J. Siteman Cancer Center?Barnes Jewish Hospital Foundation Cancer Frontier Fund, NIH National Cancer Institute P30 CA091842 and R01 CA246208, and the Barnard Trust. Z.-F.M. designed and performed experiments, analyzed and interpreted data, performed statistical analyses, and drafted and revised the manuscript; M.A.L. designed and performed experiments and bioinformatic analyses, analyzed and interpreted data, and performed statistical analyses; C.J.C. designed and performed experiments, analyzed and interpreted data, and performed statistical analyses; M.A.-T. performed experiments, analyzed and interpreted data, performed statistical analyses, and revised the manuscript; D.P. designed and performed experiments, analyzed and interpreted data, and performed statistical analyses; J.W.B. performed computational work on evolutionary conservation and structure-function analysis; J.-X.S. performed experiments, analyzed and interpreted data, and performed statistical analyses; J.R.B. S.K. and J.L. performed experiments and analyzed data; M.M. designed and performed experiments and analyzed data; I.V. and L.A.H. provided critical reagent and revised manuscript; N.O.D. provided funding and critical reagent; V.C. provided funding, a critical reagent, and revised manuscript; D.C.R. provided funding, interpreted data, and revised the manuscript; Z.N.-W. provided funding and human samples for the study and drafted and revised the manuscript; J.C.M. designed the experiments, provided funding for the study, performed bioinformatic analyses, generated data, and drafted and revised the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = oct,
day = "26",
doi = "10.1016/j.devcel.2020.07.005",
language = "English",
volume = "55",
pages = "178--194.e7",
journal = "Developmental Cell",
issn = "1534-5807",
number = "2",
}