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.

Gradual Rarefaction of Hematopoietic Precursors and Atrophy in a Depleted microRNA 29a, b and c Environment

“…Moreover, while we show that the miR29b2c knockout does not have the same phenotype as miR29ab1, we also are able to prove that when both miR29 clusters are deleted a marked decrease of organ and body size ensues, accompanied by a far more drastic diminution of the hematopoietic stem cells. Our results seem to be confirmed by recent work that shows miR29 to be involved in organ and body growth [ 12 ]. Therefore, we believe that the prior publication by Hu et al only represents a partial depiction of the consequences of miR29 deletion and that our report is a more detailed account to date of the effects of the deletion of not one but both miR29 clusters.…”

Cardiac myocyte miR-29 promotes pathological remodeling of the heart by activating Wnt signaling

“…3a ). This is consistent with previous reports 22 , 33 and interesting with regard to a proposed function of miR-29 in body growth control 33 . Most remarkable with respect to disease, however, are the temporal changes in miR-29 expression that occur in mice subjected to TAC.…”

miR-29b overexpression induces cochlear hair cell apoptosis through the regulation of SIRT1/PGC-1α signaling: Implications for age-related hearing loss

“…Recently, alterations in the expression of the miR-29 family and the miR-34 family have been documented during aging in the mammalian inner ear ( 8 , 9 ). Of interest is that miR-29b has been shown to be involved in cellular senescence and the apoptosis of nerve cell lines, the brain and the liver during aging ( 10 , 11 ). However, the functions of miR-29b regarding apoptosis are not yet fully understood.…”