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Molecular and Cellular Biology, November 2003, p. 8255-8271, Vol. 23, No. 22
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.22.8255-8271.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Female Lethality and Apoptosis of Spermatocytes in Mice Lacking the UBR2 Ubiquitin Ligase of the N-End Rule Pathway

Yong Tae Kwon,1* Zanxian Xia,2 Jee Young An,1 Takafumi Tasaki,1 Ilia V. Davydov,2,{dagger} Jai Wha Seo,1 Jun Sheng,2 Youming Xie,2,{ddagger} and Alexander Varshavsky2

Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261,1 Division of Biology, California Institute of Technology, Pasadena, California 911252

Received 5 June 2003/ Returned for modification 21 July 2003/ Accepted 5 August 2003

Substrates of the ubiquitin-dependent N-end rule pathway include proteins with destabilizing N-terminal residues. UBR1-/- mice, which lacked the pathway's ubiquitin ligase E3{alpha}, were viable and retained the N-end rule pathway. The present work describes the identification and analysis of mouse UBR2, a homolog of UBR1. We demonstrate that the substrate-binding properties of UBR2 are highly similar to those of UBR1, identifying UBR2 as the second E3 of the mammalian N-end rule pathway. UBR2-/- mouse strains were constructed, and their viability was found to be dependent on both gender and genetic background. In the strain 129 (inbred) background, the UBR2-/- genotype was lethal to most embryos of either gender. In the 129/B6 (mixed) background, most UBR2-/- females died as embryos, whereas UBR2-/- males were viable but infertile, owing to the postnatal degeneration of the testes. The gross architecture of UBR2-/- testes was normal and spermatogonia were intact as well, but UBR2-/- spermatocytes were arrested between leptotene/zygotene and pachytene and died through apoptosis. A conspicuous defect of UBR2-/- spermatocytes was the absence of intact synaptonemal complexes. We conclude that the UBR2 ubiquitin ligase and, hence, the N-end rule pathway are required for male meiosis and spermatogenesis and for an essential aspect of female embryonic development.

* Corresponding author. Mailing address: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, 3501 Terrace St., Pittsburgh, PA 15261. Phone: (412) 383-7994. Fax: (412) 648-1664. E-mail: yok5{at}pitt.edu.

{dagger} Present address: IGEN, Inc., Gaithersburg, MD 20877.

{ddagger} Present address: Department of Pathology, School of Medicine, Wayne State University, Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201.

Molecular and Cellular Biology, November 2003, p. 8255-8271, Vol. 23, No. 22
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.22.8255-8271.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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