The RNA-binding protein Musashi is required intrinsically to maintain stem cell identity

doi:10.1073/pnas.0600906103

The RNA-binding protein Musashi is required intrinsically to maintain stem cell identity

*Department of Anatomy and Cell Biology, University of Melbourne, Melbourne VIC 3010, Australia;
^‡School of Environmental and Life Sciences, University of Newcastle, Callaghan NSW 2308, Australia; and
^†Australian Research Council Centre of Excellence in Biotechnology and Development, Callaghan NSW 2308, Australia

Edited by Anthony P. Mahowald, University of Chicago, Chicago, IL, and approved March 10, 2006 (received for review February 2, 2006)

Abstract

A key goal of regenerative medicine is an understanding of the genetic factors that define the properties of stem cells. However, stem cell research in mammalian tissue has been hampered by a paucity of stem cell-specific markers. Although increasing evidence suggests that members of the Musashi (Msi) family of RNA-binding proteins play important functions in progenitor cells, it remains unclear whether there is a stem cell-autonomous requirement for Msi because of an inability to distinguish stem cells from early-lineage cells in mammalian tissues. Here, using the Drosophila testis as a model system for the study of stem cell regulation, we show specific evidence for a cell-autonomous requirement for Msi family proteins in regulating stem cell differentiation, leading to the identification of an RNA-binding protein required for spermatogonial stem cell maintenance. We found that loss of Msi function disrupts the balance between germ-line stem cell renewal and differentiation, resulting in the premature differentiation of germ-line stem cells. Moreover, we found that, although Msi is expressed in both somatic and germ cells, Msi function is required intrinsically in stem cells for maintenance of stem cell identity. We also discovered a requirement for Msi function in male meiosis, revealing that Msi has distinct roles at different stages of germ cell differentiation. We describe the complementary expression patterns of the murine Msi paralogues Msi1 and Msi2 during spermatogenesis, which support the idea of distinct, evolutionarily conserved roles of Msi.

Footnotes

^§To whom correspondence should be addressed. E-mail: g.hime{at}unimelb.edu.au
Author contributions: N.A.S., E.A.M., and G.R.H. designed research; N.A.S., E.A.M., N.L.M., and G.R.H. performed research; N.A.S., E.A.M., and G.R.H. analyzed data; and N.A.S., E.A.M., and G.R.H. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

Abbreviations:

GSC,

germ-line stem cell;

CPC,

cyst progenitor cell;

Msi,

Musashi.