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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

A Mouse Model of Targeted Musashi1 Expression in Whole Intestinal Epithelium Suggests Regulatory Roles in Cell Cycle and Stemness

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Cambuli, F. M. [1] ; Correa, B. R. [2, 3] ; Rezza, A. [1] ; Burns, S. C. [2] ; Qiao, M. [2] ; Uren, P. J. [4] ; Kress, E. [1] ; Boussouar, A. [1] ; Galante, P. A. F. [3] ; Penalva, L. O. F. [2, 5] ; Plateroti, M. [1]
Total Authors: 11
[1] Univ Lyon, Ctr Genet & Physiol Mol & Cellulaire, Lyon - France
[2] Univ Texas Hlth Sci Ctr San Antonio, Childrens Canc Res Inst, San Antonio, TX - USA
[3] Hosp Sirio Libanes, Ctr Oncol Mol, Sao Paulo - Brazil
[4] Univ So Calif, Div Biol Sci, Mol & Computat Biol Sect, Los Angeles, CA - USA
[5] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX - USA
Total Affiliations: 5
Document type: Journal article
Source: Stem Cells; v. 33, n. 12, SI, p. 3621-3634, DEC 2015.
Web of Science Citations: 11

The intestinal epithelium is very peculiar for its continuous cell renewal, fuelled by multipotent stem cells localized within the crypts of Lieberkuhn. Several lines of evidence have established the evolutionary conserved RNA-binding protein Musashi1 as a marker of adult stem cells, including those of the intestinal epithelium, and revealed its roles in stem cell self-renewal and cell fate determination. Previous studies from our laboratories have shown that Musashi1 controls stem cell-like features in medulloblastoma, glioblastoma, and breast cancer cells, and has pro-proliferative and pro-tumorigenic properties in intestinal epithelial progenitor cells in vitro. To undertake a detailed study of Musashi1's function in the intestinal epithelium in vivo, we have generated a mouse model, referred to as v-Msi, overexpressing Musashi1 specifically in the entire intestinal epithelium. Compared with wild type litters, v-Msi1 mice exhibited increased intestinal crypt size accompanied by enhanced proliferation. Comparative transcriptomics by RNA-seq revealed Musashi1's association with gut stem cell signature, cell cycle, DNA replication, and drug metabolism. Finally, we identified and validated three novel mRNA targets that are stabilized by Musashi1, Ccnd1 (Cyclin D1), Cdk6, and Sox4. In conclusion, the targeted expression of Musashi1 in the intestinal epithelium in vivo increases the cell proliferation rate and strongly suggests its action on stem cells activity. This is due to the modulation of a complex network of gene functions and pathways including drug metabolism, cell cycle, and DNA synthesis and repair. (AU)

FAPESP's process: 13/07159-5 - RNA-binding proteins and post-transcriptional variations: influence on glioblastoma multiforme development
Grantee:Bruna Renata Silva Corrêa
Support type: Scholarships in Brazil - Doctorate