Musashi1 targeted expression in murine intestine. A mouse model of targeted Musashi1 expression in whole intestinal epithelium unveils its major roles in cell cycle and stemness

Background. The intestinal epithelium is very peculiar for its continuous and rapid cell renewal, fuelled by multipotent stem cells localized within the crypts of Lieberkühn. Several data support the evolutionary conserved RNA-binding protein Musashi1 as a marker of adult stem cells including those of the intestinal epithelium and roles in stem cell self-renewal and cell fate determination. Previous study from our laboratories showed 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. With the aim to study in detail the function of Musashi1 in the intestinal epithelium in vivo, we generated a mouse model targeting Musashi1 expression along the antero-posterior and the vertical epithelial axes. Methods. We generated mice expressing Musashi1 specifically in the intestinal epithelium, the v-Msi1 animals. We used RNA-Seq to define Musashi1-dependent molecular signatures and conducted further validations in 293T cells. Results. Compared with wild type litters, v-Msi1 mice showed an increased size of the intestinal crypts accompanied by enhanced proliferation and stem activity. Comparative transcription profile associated Musashi1 with stem cell activity, cell cycle, DNA replication and drug metabolism. Finally, we identified three novel mRNA targets that are stabilized by Musashi1, Cyclin D1, CDK6 and Sox4. Conclusion. The targeted expression of Msi1 in the intestinal epithelium in vivo increases the cell proliferation rate and the activity of the stem cells. This is due to a complex network of gene functions and pathways including drug metabolism, cell cycle and DNA synthesis and repair.