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Molecular and Cellular Biology, December 2003, p. 9150-9161, Vol. 23, No. 24
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.24.9150-9161.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Generation and Analysis of Siah2 Mutant Mice

Ian J. Frew,1 Vicki E. Hammond,2 Ross A. Dickins,1 Julian M. W. Quinn,3 Carl R. Walkley,1,4 Natalie A. Sims,3 Ralf Schnall,1 Neil G. Della,2 Andrew J. Holloway,1 Matthew R. Digby,1 Peter W. Janes,1 David M. Tarlinton,5 Louise E. Purton,1 Matthew T. Gillespie,3 and David D. L. Bowtell1,6*

Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, East Melbourne, Victoria 3002,1 St. Vincent's Institute for Medical Research, Fitzroy, Victoria 3065,3 Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050,5 Howard Florey InstituteDepartments of,2 Medicine,4 Biochemistry,The University of Melbourne, Parkville, Victoria 3010, Australia6

Received 8 May 2003/ Returned for modification 10 July 2003/ Accepted 3 September 2003

Siah proteins function as E3 ubiquitin ligase enzymes to target the degradation of diverse protein substrates. To characterize the physiological roles of Siah2, we have generated and analyzed Siah2 mutant mice. In contrast to Siah1a knockout mice, which are growth retarded and exhibit defects in spermatogenesis, Siah2 mutant mice are fertile and largely phenotypically normal. While previous studies implicate Siah2 in the regulation of TRAF2, Vav1, OBF-1, and DCC, we find that a variety of responses mediated by these proteins are unaffected by loss of Siah2. However, we have identified an expansion of myeloid progenitor cells in the bone marrow of Siah2 mutant mice. Consistent with this, we show that Siah2 mutant bone marrow produces more osteoclasts in vitro than wild-type bone marrow. The observation that combined Siah2 and Siah1a mutation causes embryonic and neonatal lethality demonstrates that the highly homologous Siah proteins have partially overlapping functions in vivo.

* Corresponding author. Mailing address: Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett St., Victoria 8006, Australia. Phone: 61 3 9656 1296. Fax: 61 3 9656 1411. E-mail: d.bowtell{at}petermac.org.

Molecular and Cellular Biology, December 2003, p. 9150-9161, Vol. 23, No. 24
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.24.9150-9161.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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