Author
Listed:
- Maddalena Adorno
(Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine)
- Shaheen Sikandar
(Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine)
- Siddhartha S. Mitra
(Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine)
- Angera Kuo
(Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine)
- Benedetta Nicolis di Robilant
(Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
International PhD School in Molecular Medicine, San Raffaele University)
- Veronica Haro-Acosta
(Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine)
- Youcef Ouadah
(Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
Program in Cancer Biology, Stanford University School of Medicine)
- Marco Quarta
(Stanford University School of Medicine)
- Jacqueline Rodriguez
(Stanford University School of Medicine)
- Dalong Qian
(Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine)
- Vadiyala M. Reddy
(Stanford University School of Medicine)
- Samuel Cheshier
(Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
Stanford University School of Medicine)
- Craig C. Garner
(Stanford University School of Medicine)
- Michael F. Clarke
(Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine)
Abstract
Down’s syndrome results from full or partial trisomy of chromosome 21. However, the consequences of the underlying gene–dosage imbalance on adult tissues remain poorly understood. Here we show that in Ts65Dn mice, which are trisomic for 132 genes homologous to genes on human chromosome 21, triplication of Usp16 reduces the self-renewal of haematopoietic stem cells and the expansion of mammary epithelial cells, neural progenitors and fibroblasts. In addition, Usp16 is associated with decreased ubiquitination of Cdkn2a and accelerated senescence in Ts65Dn fibroblasts. Usp16 can remove ubiquitin from histone H2A on lysine 119, a critical mark for the maintenance of multiple somatic tissues. Downregulation of Usp16, either by mutation of a single normal Usp16 allele or by short interfering RNAs, largely rescues all of these defects. Furthermore, in human tissues overexpression of USP16 reduces the expansion of normal fibroblasts and postnatal neural progenitors, whereas downregulation of USP16 partially rescues the proliferation defects of Down’s syndrome fibroblasts. Taken together, these results suggest that USP16 has an important role in antagonizing the self-renewal and/or senescence pathways in Down’s syndrome and could serve as an attractive target to ameliorate some of the associated pathologies.
Suggested Citation
Maddalena Adorno & Shaheen Sikandar & Siddhartha S. Mitra & Angera Kuo & Benedetta Nicolis di Robilant & Veronica Haro-Acosta & Youcef Ouadah & Marco Quarta & Jacqueline Rodriguez & Dalong Qian & Vadi, 2013.
"Usp16 contributes to somatic stem-cell defects in Down’s syndrome,"
Nature, Nature, vol. 501(7467), pages 380-384, September.
Handle:
RePEc:nat:nature:v:501:y:2013:i:7467:d:10.1038_nature12530
DOI: 10.1038/nature12530
Download full text from publisher
As the access to this document is restricted, you may want to search for a different version of it.
Corrections
All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:501:y:2013:i:7467:d:10.1038_nature12530. See general information about how to correct material in RePEc.
If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.
We have no bibliographic references for this item. You can help adding them by using this form .
If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.
For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .
Please note that corrections may take a couple of weeks to filter through
the various RePEc services.