Authors

R. Q. Liang; A. Khanna; S. Muthusamy; N. Li; H. Sarojini; J. J. Kopchick; M. M. Masternak; A. Bartke;E. N. Wang

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Abbreviated Journal Title

Aging Cell

Keywords

microRNA; aging; IGF1; IGF1R; growth hormone; Ames dwarf mice and GHRKO; mice; miR-470; miR-669b; miR-681; cognitive robustness and longevity; Cell Biology; Geriatrics & Gerontology

Abstract

Long-lived mutant mice, both Ames dwarf and growth hormone receptor genedisrupted or knockout strains, exhibit heightened cognitive robustness and altered IGF1 signaling in the brain. Here, we report, in both these long-lived mice, that three up-regulated lead microRNAs, miR-470, miR-669b, and miR-681, are involved in posttranscriptional regulation of genes pertinent to growth hormone/IGF1 signaling. All three are most prominently localized in the hippocampus and correspond to reduced expression of key IGF1 signaling genes: IGF1, IGF1R, and PI3 kinase. The decline in these genes expression translates into decreased phosphorylation of downstream molecules AKT and FoxO3a. Cultures transfected with either miR-470, miR-669b, or miR-681 show repressed endogenous expression of all three genes of the IGF1 signaling axis, most significantly IGF1R, while other similarly up-regulated microRNAs, including let-7g and miR-509, do not induce the same levels of repression. Transduction study in IGF1-responsive cell cultures shows significantly reduced IGF1R expression, and AKT to some extent, most notably by miR-681. This is accompanied by decreased levels of downstream phosphorylated forms of AKT and FoxO3a upon IGF1 stimulation. Suppression of IGF1R by the three microRNAs is further validated by IGF1R 3'UTR reporter assays. Taken together, our results suggest that miR-470, miR-669b, and miR-681 are all functionally able to suppress IGF1R and AKT, two upstream genes controlling FoxO3a phosphorylation status. Their up-regulation in growth hormone signaling-deficient mutant mouse brain suggests reduced IGF1 signaling at the posttranscriptional level, for numerous gains of neuronal function in these long-lived mice.

Journal Title

Aging Cell

Volume

10

Issue/Number

6

Publication Date

1-1-2011

Document Type

Article

Language

English

First Page

1080

Last Page

1088

WOS Identifier

WOS:000297003800017

ISSN

1474-9718

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