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Loss of the RNA binding protein HuR in early murine limb mesenchyme does not affect development but leads to impaired bone homeostasis in adulthood
Fu, Shijian Johnson, Kirsty A. Winstanley‐Zarach, Phaedra Ersoy, Ufuk Adlmanninger, Elena McDermott, Benjamin T. Keenan, Craig Vasilaki, Aphrodite Kanakis, Ioannis Milner, Peter I.
Fu, Shijian
Johnson, Kirsty A.
Winstanley‐Zarach, Phaedra
Ersoy, Ufuk
Adlmanninger, Elena
McDermott, Benjamin T.
Keenan, Craig
Vasilaki, Aphrodite
Kanakis, Ioannis
Milner, Peter I.
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University of Liverpool; Edge Hill University; University of Chester; Vanthof Scientific, Poland; Biomedical Sciences Research Centre “Alexander Fleming”, Greece; University of Thessaloniki
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Publication Date
2025-11-20
Submitted Date
2025-03-24
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Abstract
In this study, we examined how a critical posttranscriptional regulator, the RNA‐binding protein HuR (gene name Elavl1), contributes to the development and maintenance of limb skeletal tissue. Using the Prx1‐Cre knockout model, we examined the effect of germline knockout (Elavl1KO) and limb mesenchyme‐specific knockout (MSC‐Elavl1KO) of HuR on limb development. We found that Elavl1KO disrupted the development of the limb skeleton and was associated with a loss of signaling from the apical ectodermal ridge (AER). In contrast, MSC‐Elavl1KO did not appear to affect skeletal development. Mature MSC‐Elavl1KO mice appeared healthy, but their limb skeleton exhibited abnormal bone structure in both males and females at 2.5 months of age. Osteoblasts isolated from MSC‐Elavl1KO mice exhibited lower expression of osteoblastic marker genes, and their ability to generate a mineralized matrix was markedly impaired. RNA‐Seq analysis of these osteoblasts demonstrated that loss of HuR substantially influenced their transcriptome, affecting genes associated with a wide range of cellular processes. Finally, using siRNA knockdown in the human MG63 cell line, we identified that loss of HuR leads to increased mRNA turnover of the osteoblastic transcription factor Runx2. Overall, the study has demonstrated a critical role for HuR‐mediated posttranscriptional control in skeletal development and homeostasis, but finds that its expression in mesenchyme‐derived cells only becomes critical in mature skeletal tissue.
Citation
Fu, S., Johnson, K. A., Winstanley-Zarach, P., Ersoy, U., Adlmanninger, E., McDermott, B. T., Keenan, C., Vasilaki, A., Kanakis, I., Milner, P. I., van’t Hof, R. J., Kontoyiannis, D., Bou-Gharios, G., Turner, D. A., & Tew, S. R. (2025). Loss of the RNA binding protein HuR in early murine limb mesenchyme does not affect development but leads to impaired bone homeostasis in adulthood. The FASEB Journal, 39(22), e71222. https://doi.org/https://doi.org/10.1096/fj.202500780RR
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Wiley
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The FASEB Journal
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Article
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© 2025 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
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0892-6638
EISSN
1530-6860
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This work was supported by the China Scholarship Council (CSC) (202108230116). UKRI|Medical Research Council (MRC) (MR/N011333/1, MR/R502182/1), UKRI|Biotechnology and Biological Sciences Research Council (BBSRC), (BB/R01390X/1), Vivensa Foundation (DMT) (RPGF2002\217).