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Molecular and Cellular Biology, October 2003, p. 6798-6808, Vol. 23, No. 19
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.19.6798-6808.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

COP9 Signalosome Subunit 3 Is Essential for Maintenance of Cell Proliferation in the Mouse Embryonic Epiblast

Jiong Yan,1 Katherina Walz,1 Hisashi Nakamura,1 Sandra Carattini-Rivera,1 Qi Zhao,1,{dagger} Hannes Vogel,2 Ning Wei,3 Monica J. Justice,1 Allan Bradley,4 and James R. Lupski1,5,6*

Department of Molecular and Human Genetics,1 Department of Pediatrics, Baylor College of Medicine,5 Texas Children's Hospital, Houston, Texas,6 Department of Pathology, Stanford University, Stanford, California,2 Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut,3 Sanger Centre, Cambridge, United Kingdom4

Received 17 April 2003/ Returned for modification 19 May 2003/ Accepted 27 June 2003

Csn3 (Cops3) maps to the mouse chromosome 11 region syntenic to the common deletion interval for the Smith-Magenis syndrome, a contiguous gene deletion syndrome. It encodes the third subunit of an eight-subunit protein complex, the COP9 signalosome (CSN), which controls a wide variety of molecules of different functions. Mutants of this complex caused lethality at early development of both plants and Drosophila melanogaster. CSN function in vivo in mammals is unknown. We disrupted the murine Csn3 gene in three independent ways with insertional vectors, including constructing a {approx}3-Mb inversion chromosome. The heterozygous mice appeared normal, although the protein level was reduced. Csn3-/- embryos arrested after 5.5 days postcoitum (dpc) and resorbed by 8.5 dpc. Mutant embryos form an abnormal egg cylinder which does not gastrulate. They have reduced numbers of epiblast cells, mainly due to increased cell death. In the Csn3-/- mice, subunit 8 of the COP9 complex was not detected by immunohistochemical techniques, suggesting that the absence of Csn3 may disrupt the entire COP9 complex. Therefore, Csn3 is important for maintaining the integrity of the COP9 signalosome and is crucial to maintain the survival of epiblast cells and thus the development of the postimplantation embryo in mice.

* Corresponding author. Mailing address: Dept. of Molecular & Human Genetics, Baylor College of Medicine, Room 604B, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-6530. Fax: (713) 798- 5073. E-mail: jlupski{at}bcm.tmc.edu.

{dagger} Present address: Celera Genomics, Rockville, MD 20850.

Molecular and Cellular Biology, October 2003, p. 6798-6808, Vol. 23, No. 19
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.19.6798-6808.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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