title: Evidence That Up-Regulation of MicroRNA-29 Contributes to Postnatal Body Growth Deceleration.
abstract: Body growth is rapid in infancy but subsequently slows and eventually ceases due to a progressive decline in cell proliferation that occurs simultaneously in multiple organs. We previously showed that this decline in proliferation is driven in part by postnatal down-regulation of a large set of growth-promoting genes in multiple organs. We hypothesized that this growth-limiting genetic program is orchestrated by microRNAs (miRNAs). Bioinformatic analysis identified target sequences of the miR-29 family of miRNAs to be overrepresented in age-down-regulated genes. Concomitantly, expression microarray analysis in mouse kidney and lung showed that all members of the miR-29 family, miR-29a, -b, and -c, were strongly up-regulated from 1 to 6 weeks of age. Real-time PCR confirmed that miR-29a, -b, and -c were up-regulated with age in liver, kidney, lung, and heart, and their expression levels were higher in hepatocytes isolated from 5-week-old mice than in hepatocytes from embryonic mouse liver at embryonic day 16.5. We next focused on 3 predicted miR-29 target genes (Igf1, Imp1, and Mest), all of which are growth-promoting. A 3'-untranslated region containing the predicted target sequences from each gene was placed individually in a luciferase reporter construct. Transfection of miR-29 mimics suppressed luciferase gene activity for all 3 genes, and this suppression was diminished by mutating the target sequences, suggesting that these genes are indeed regulated by miR-29. Taken together, the findings suggest that up-regulation of miR-29 during juvenile life drives the down-regulation of multiple growth-promoting genes, thus contributing to physiological slowing and eventual cessation of body growth.
authors: Section on Growth and Development (F.K., A.A.N., G.R., J.B., J.C.L.) and Section on Neuroendocrinology (S.J.C.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; and Center for Molecular Medicine and Pediatric Endocrinology Unit (A.C.A., O.N.), Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors: Fariha
authors: F
authors: Kamran
authors: Section on Growth and Development (F.K., A.A.N., G.R., J.B., J.C.L.) and Section on Neuroendocrinology (S.J.C.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; and Center for Molecular Medicine and Pediatric Endocrinology Unit (A.C.A., O.N.), Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors: Anenisia C
authors: AC
authors: Andrade
authors: Section on Growth and Development (F.K., A.A.N., G.R., J.B., J.C.L.) and Section on Neuroendocrinology (S.J.C.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; and Center for Molecular Medicine and Pediatric Endocrinology Unit (A.C.A., O.N.), Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors: Aikaterini A
authors: AA
authors: Nella
authors: Section on Growth and Development (F.K., A.A.N., G.R., J.B., J.C.L.) and Section on Neuroendocrinology (S.J.C.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; and Center for Molecular Medicine and Pediatric Endocrinology Unit (A.C.A., O.N.), Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors: Samuel J
authors: SJ
authors: Clokie
authors: Section on Growth and Development (F.K., A.A.N., G.R., J.B., J.C.L.) and Section on Neuroendocrinology (S.J.C.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; and Center for Molecular Medicine and Pediatric Endocrinology Unit (A.C.A., O.N.), Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors: Geoffrey
authors: G
authors: Rezvani
authors: Section on Growth and Development (F.K., A.A.N., G.R., J.B., J.C.L.) and Section on Neuroendocrinology (S.J.C.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; and Center for Molecular Medicine and Pediatric Endocrinology Unit (A.C.A., O.N.), Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors: Ola
authors: O
authors: Nilsson
authors: Section on Growth and Development (F.K., A.A.N., G.R., J.B., J.C.L.) and Section on Neuroendocrinology (S.J.C.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; and Center for Molecular Medicine and Pediatric Endocrinology Unit (A.C.A., O.N.), Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors: Jeffrey
authors: J
authors: Baron
authors: Section on Growth and Development (F.K., A.A.N., G.R., J.B., J.C.L.) and Section on Neuroendocrinology (S.J.C.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; and Center for Molecular Medicine and Pediatric Endocrinology Unit (A.C.A., O.N.), Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors: Julian C
authors: JC
authors: Lui
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000375:Aging / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D015536:Down-Regulation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D048788:Growth and Development / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009206:Myocardium / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D009928:Organ Specificity / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; C547014:MIRN29 microRNA, mouse; D035683:MicroRNAs; D012333:RNA, Messenger