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Molecular and Cellular Biology, April 2002, p. 2294-2303, Vol. 22, No. 7
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.7.2294-2303.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The Ubiquitin Ligase Component Siah1a Is Required for Completion of Meiosis I in Male Mice

Ross A. Dickins,1 Ian J. Frew,1,2 Colin M. House,1 Moira K. O'Bryan,3 Andrew J. Holloway,1 Izhak Haviv,1 Nadia Traficante,1 David M. de Kretser,3 and David D. L. Bowtell1,4*

Peter MacCallum Cancer Institute, East Melbourne, Victoria 3002,1 Department of Pathology,2 Department of Biochemistry, University of Melbourne, Parkville, Victoria 3010,4 Monash Institute of Reproduction and Development, Monash University, Clayton, Victoria 3168, Australia3

Received 22 August 2001/ Returned for modification 26 October 2001/ Accepted 27 December 2001

The mammalian Siah genes encode highly conserved proteins containing a RING domain. As components of E3 ubiquitin ligase complexes, Siah proteins facilitate the ubiquitination and degradation of diverse protein partners including ß-catenin, N-CoR, and DCC. We used gene targeting in mice to analyze the function of Siah1a during mammalian development and reveal novel roles in growth, viability, and fertility. Mutant animals have normal weights at term but are postnatally growth retarded, despite normal levels of pituitary growth hormone. Embryonic fibroblasts isolated from mutant animals grow normally. Most animals die before weaning, and few survive beyond 3 months. Serum gonadotropin levels are normal in Siah1a mutant mice; however, females are subfertile and males are sterile due to a block in spermatogenesis. Although spermatocytes in mutant mice display normal meiotic prophase and meiosis I spindle formation, they accumulate at metaphase to telophase of meiosis I and subsequently undergo apoptosis. The requirement of Siah1a for normal progression beyond metaphase I suggests that Siah1a may be part of a novel E3 complex acting late in the first meiotic division.

* Corresponding author. Mailing address: Peter MacCallum Cancer Institute, St. Andrew's Place, East Melbourne, Victoria 3002, Australia. Phone: 61 3 9656 1296. Fax: 61 3 9656 1411. E-mail: d.bowtell{at}pmci.unimelb.edu.au.

Molecular and Cellular Biology, April 2002, p. 2294-2303, Vol. 22, No. 7
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.7.2294-2303.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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