The Mouse Polyubiquitin Gene Ubb Is Essential for Meiotic Progression

Abstract

Ubiquitin is encoded in mice by two polyubiquitin genes, Ubb and Ubc, that are considered to be stress inducible and two constitutively expressed monoubiquitin (Uba) genes. Here we report that targeted disruption of Ubb results in male and female infertility due to failure of germ cells to progress through meiosis I and hypogonadism. In the absence of Ubb, spermatocytes and oocytes arrest during meiotic prophase, before metaphase of the first meiotic division. Although cellular ubiquitin levels are believed to be maintained by a combination of functional redundancy among the four ubiquitin genes, stress inducibility of the two polyubiquitin genes, and ubiquitin recycling by proteasome-associated isopeptidases, our results indicate that ubiquitin is required for and consumed during meiotic progression. The striking similarity of the meiotic phenotype in Ubb^−/− germ cells to the sporulation defect in fission yeast (Schizosaccharomyces pombe) lacking a polyubiquitin gene suggests that a meiotic role of the polyubiquitin gene has been conserved throughout eukaryotic evolution.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://mcb.asm.org/ .

ACKNOWLEDGMENTS

We thank our colleagues in the Kopito lab for helpful discussions and comments, and we are especially grateful to Catherine Gilchrist for help in screening the mouse genomic DNA library and Gregory Barsh for helpful discussion. We also thank the Transgenic Research Center for DNA microinjection, embryonic stem cell manipulation, and generation of chimeric mice.

This work was funded in part by a grant from the National Institute of Aging (to R.R.K.) and by grants from the National Institute of Child Health and Human Development (to M.A.H. and M.C.).