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Molecular and Cellular Biology, March 2009, p. 1498-1505, Vol. 29, No. 6
0270-7306/09/$08.00+0     doi:10.1128/MCB.01778-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Preimplantation Mouse Embryos Depend on Inhibitory Phosphorylation of Separase To Prevent Chromosome Missegregation{triangledown}

Xingxu Huang,1* Claudia V. Andreu-Vieyra,2 Meizhi Wang,1 Austin J. Cooney,3 Martin M. Matzuk,4 and Pumin Zhang4,5*

Model Animal Research Center, Nanjing University, Nanjing, China,1 Department of Pathology,2 Department of Cell and Molecular Biology,3 Department of Molecular Physiology and Biophysics,4 Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 770305

Received 20 November 2008/ Returned for modification 19 December 2008/ Accepted 23 December 2008

Separase is a critical protease that catalyzes the cleavage of sister chromatid cohesins to allow the separation of sister chromatids in the anaphase. Its activity must be inhibited prior to the onset of the anaphase. Two inhibitory mechanisms exist in vertebrates that block the protease activity. One mechanism is through binding and inhibition by securin, and another is phosphorylation on Ser1126 (in humans [Ser1121 in mice]). These two mechanisms are largely redundant. However, phosphorylation on Ser1121 is critical for the prevention of premature sister separation in embryonic germ cells. As a result, Ser1121-to-Ala mutation leads to depletion of germ cells in development and subsequently to infertility in mice. Here, we report that the same mutation also causes embryogenesis failure between the 8- and 16-cell stages in mice. Our results indicate a critical role of separase phosphorylation in germ cell development as well as in early embryogenesis. Thus, deregulation of separase may be a significant contributor to infertility in humans.

* Corresponding author. Mailing address for Pumin Zhang: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-1866. Fax: (713) 798-3475. E-mail: pzhang{at}bcm.tmc.edu. Mailing address for Xingxu Huang: Model Animal Research Center, Nanjing University, 12 Xuefu Road, Pukou District, Nanjing 210061, People's Republic of China. Phone: 86-25-58641517. Fax: 86-25-58641500. E-mail: huangxx{at}nicemice.cn

{triangledown} Published ahead of print on 5 January 2009.

Molecular and Cellular Biology, March 2009, p. 1498-1505, Vol. 29, No. 6
0270-7306/09/$08.00+0     doi:10.1128/MCB.01778-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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