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Molecular and Cellular Biology, April 2005, p. 2995-3006, Vol. 25, No. 8
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.8.2995-3006.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Scaffold Attachment Factor B1 Functions in Development, Growth, and Reproduction

Margarita Ivanova, Klaudia M. Dobrzycka, Shiming Jiang, Kai Michaelis, Rene Meyer, Kaiyan Kang, Brian Adkins, Oleg A. Barski, Simeen Zubairy, Jana Divisova, Adrian V. Lee, and Steffi Oesterreich^*

Departments of Medicine and Molecular and Cellular Biology, Breast Center, Baylor College of Medicine, and Methodist Hospital, Houston, Texas

Received 22 September 2004/ Returned for modification 20 November 2004/ Accepted 30 December 2004

Scaffold attachment factor B1 (SAFB1) is a multifunctional protein that can bind both DNA and RNA and is involved in RNA processing and stress response. In addition, SAFB1 contains a transcriptional repression domain and can bind certain hormone receptors and repress their activity. To assess the role of SAFB1 in vivo, we generated SAFB1 mutant mice through targeted deletion in embryonic stem cells. While viable homozygous mutant (SAFB1^–/–) mice were obtained, genotypic distribution indicated that homozygous deficiency resulted in both prenatal and neonatal lethality. Mice lacking SAFB1 exhibited dwarfism, as a result of in utero growth retardation, and had low serum insulin-like growth factor 1 (IGF1) levels. In agreement with the previous characterization of SAFB1 as a corepressor for hormone receptors, we found that SAFB1^–/– mice displayed dramatic defects in the development and function of the reproductive system. Male SAFB1 null mice were infertile, apparently because of low circulating levels of testosterone. SAFB1^–/– testes were small and showed progressive degeneration of the germinal epithelium, increased apoptosis of germ cells, and Leydig cell hyperplasia. SAFB^–/– female mice were subfertile and showed progressive infertility, in part because of defects in oviductal transport and reduced numbers of follicles. Immortalized SAFB1^–/– mouse embryonic fibroblasts showed cell-intrinsic defects including increased transcriptional estrogen receptor activity and enhanced responsiveness to IGF1. Together, these in vivo findings establish a critical role for SAFB1 in development, growth regulation, and reproduction.

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* Corresponding author. Mailing address: Baylor College of Medicine, Breast Center, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-1623. Fax: (713) 798-1642. E-mail: steffio{at}breastcenter.tmc.edu.

Present address: University of Louisville, Louisville, Ky.

Present address: Institute for Molecular Biology of Infections, D-97070 Würzburg, Germany.

Present address: Howard University, Washington, D.C.

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Molecular and Cellular Biology, April 2005, p. 2995-3006, Vol. 25, No. 8
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.8.2995-3006.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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