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Molecular and Cellular Biology, October 2006, p. 7201-7210, Vol. 26, No. 19
0270-7306/06/$08.00+0     doi:10.1128/MCB.00459-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Disruption of Ledgf/Psip1 Results in Perinatal Mortality and Homeotic Skeletal Transformations

Heidi G. Sutherland,1* Kathryn Newton,1,{dagger} David G. Brownstein,2 Megan C. Holmes,3 Clémence Kress,1 Colin A. Semple,1 and Wendy A. Bickmore1

MRC Human Genetics Unit, Crewe Road, Edinburgh EH4 2XU, United Kingdom,1 Research Animal Pathology Core Facility, Queen's Medical Research Institute, Edinburgh University, Edinburgh EH16 4TJ, United Kingdom,2 Endocrinology Unit, Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh University, Edinburgh EH16 4TJ, United Kingdom3

Received 16 March 2006/ Returned for modification 25 April 2006/ Accepted 24 June 2006

PC4- and SF2-interacting protein 1 (Psip1)—also known as lens epithelium-derived growth factor (Ledgf)—is a chromatin-associated protein that has been implicated in transcriptional regulation, mRNA splicing, and cell survival in vitro, but its biological function in vivo is unknown. We identified an embryonic stem cell clone with disrupted Psip1 in a gene trap screen. The resulting Psip1-ßgeo fusion protein retains chromatin-binding activity and the PWWP and AT hook domains of the wild-type protein but is missing the highly conserved C terminus. The majority of mice homozygous for the disrupted Psip1 gene died perinatally, but some survived to adulthood and displayed a range of phenotypic abnormalities, including low fertility, an absence of epididymal fat pads, and a tendency to develop blepharitis. However, contrary to expectations, the lens epithelium was normal. The mutant mice also exhibited motor and/or behavioral defects such as hind limb clenching, reduced grip strength, and reduced locomotor activity. Finally, both Psip1–/– neonates and surviving adults had craniofacial and skeletal abnormalities. They had brachycephaly, small rib cages, and homeotic skeletal transformations with incomplete penetrance. The latter phenotypes suggest a role for Psip1 in the control of Hox expression and may also explain why PSIP1 (LEDGF) is found as a fusion partner with NUP98 in myeloid leukemias.

* Corresponding author. Mailing address: MRC Human Genetics Unit, Crewe Road, Edinburgh EH4 2XU, United Kingdom. Phone: (44) 131 332 2471. Fax: (44) 131 467 8456. E-mail: H.Sutherland{at}hgu.mrc.ac.uk.

{dagger} Present address: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109.

Molecular and Cellular Biology, October 2006, p. 7201-7210, Vol. 26, No. 19
0270-7306/06/$08.00+0     doi:10.1128/MCB.00459-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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