Lin28 Enhances Tissue Repair by Reprogramming Cellular Metabolism

SummaryRegeneration capacity declines with age, but why juvenile organisms show enhanced tissue repair remains unexplained. Lin28a, a highly conserved RNA-binding protein expressed during embryogenesis, plays roles in development, pluripotency, and metabolism. To determine whether Lin28a might influence tissue repair in adults, we engineered the reactivation of Lin28a expression in several models of tissue injury. Lin28a reactivation improved hair regrowth by promoting anagen in hair follicles and accelerated regrowth of cartilage, bone, and mesenchyme after ear and digit injuries. Lin28a inhibits let-7 microRNA biogenesis; however, let-7 repression was necessary but insufficient to enhance repair. Lin28a bound to and enhanced the translation of mRNAs for several metabolic enzymes, thereby increasing glycolysis and oxidative phosphorylation (OxPhos). Lin28a-mediated enhancement of tissue repair was negated by OxPhos inhibition, whereas a pharmacologically induced increase in OxPhos enhanced repair. Thus, Lin28a enhances tissue repair in some adult tissues by reprogramming cellular bioenergetics.PaperCli

Evidence for migration of metamorphosing larvae of Anguilla japonica in the Kuroshio

Two sampling surveys of the R/V Tansei Maru were conducted in the Kuroshio region south of Kyushu Island of Japan and to the south in the western North Pacific, to study the distribution patterns of the larval stages of the Japanese eel Anguilla japonica as they approach their recruitment areas in East Asia. Nine fully-grown premetamorphic leptocephali (49.5-58.3mm TL) were collected during November 1996 to the east of Taiwan. During November and December 2000, nine early stage glass eels (51.3-57.0mm TL, pigmentation stage II-IV) that were still in the late metamorphosis stages were collected in the Kuroshio. These findings suggest that metamorphosing Japanese eel leptocephali that recruit to the northern part of their species range migrate in the Kuroshio. They may detrain from the Kuroshio at the pigmentation stage IV-VA and begin their coastal migration

A partial nuclear genome of the Jomons who lived 3000 years ago in Fukushima, Japan

The Jomon period of the Japanese Archipelago, characterized by cord-marked ‘jomon’ potteries, has yielded abundant human skeletal remains. However, the genetic origins of the Jomon people and their relationships with modern populations have not been clarified. We determined a total of 115 million base pair nuclear genome sequences from two Jomon individuals (male and female each) from the Sanganji Shell Mound (dated 3000 years before present) with the Jomon-characteristic mitochondrial DNA haplogroup N9b, and compared these nuclear genome sequences with those of worldwide populations. We found that the Jomon population lineage is best considered to have diverged before diversification of present-day East Eurasian populations, with no evidence of gene flow events between the Jomon and other continental populations. This suggests that the Sanganji Jomon people descended from an early phase of population dispersals in East Asia. We also estimated that the modern mainland Japanese inherited <20% of Jomon peoples’ genomes. Our findings, based on the first analysis of Jomon nuclear genome sequence data, firmly demonstrate that the modern mainland Japanese resulted from genetic admixture of the indigenous Jomon people and later migrants

Precise let-7 expression levels balance organ regeneration against tumor suppression

The in vivo roles for even the most intensely studied microRNAs remain poorly defined. Here, analysis of mouse models revealed that let-7, a large and ancient microRNA family, performs tumor suppressive roles at the expense of regeneration. Too little or too much let-7 resulted in compromised protection against cancer or tissue damage, respectively. Modest let-7 overexpression abrogated MYC-driven liver cancer by antagonizing multiple let-7 sensitive oncogenes. However, the same level of overexpression blocked liver regeneration, while let-7 deletion enhanced it, demonstrating that distinct let-7 levels can mediate desirable phenotypes. let-7 dependent regeneration phenotypes resulted from influences on the insulin-PI3K-mTOR pathway. We found that chronic high-dose let-7 overexpression caused liver damage and degeneration, paradoxically leading to tumorigenesis. These dose-dependent roles for let-7 in tissue repair and tumorigenesis rationalize the tight regulation of this microRNA in development, and have important implications for let-7 based therapeutics. DOI: http://dx.doi.org/10.7554/eLife.09431.00

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京都大学0048新制・課程博士博士(医学)甲第12925号医博第3085号新制||医||946(附属図書館)UT51-2007-H198京都大学大学院医学研究科内科系専攻(主査)教授 生田 宏一, 教授 前川 平, 教授 長澤 丘司学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA