Disruption of Ini1 Leads to Peri-Implantation Lethality and Tumorigenesis in Mice

Abstract

SNF5/INI1 is a component of the ATP-dependent chromatin remodeling enzyme family SWI/SNF. Germ line mutations ofINI1 have been identified in children with brain and renal rhabdoid tumors, indicating that INI1 is a tumor suppressor. Here we report that disruption of Ini1 expression in mice results in early embryonic lethality. Ini1-null embryos die between 3.5 and 5.5 days postcoitum, and Ini1-null blastocysts fail to hatch, form the trophectoderm, or expand the inner cell mass when cultured in vitro. Furthermore, we report that approximately 15% ofIni1-heterozygous mice present with tumors, mostly undifferentiated or poorly differentiated sarcomas. Tumor formation is associated with a loss of heterozygocity at the Ini1 locus, characterizing Ini1 as a tumor suppressor in mice. Thus, Ini1 is essential for embryo viability and for repression of oncogenesis in the adult organism.

ACKNOWLEDGMENTS

We thank J. Castillo and D. Hill for help in preparing the manuscript. We also thank A. Fraire and R. Hesselton for assistance with histopathology.

This work was supported in part by grants from the NIH to A.N.I. and S.N.J. A.N.I. is supported by a Scholar Award from the Leukemia and Lymphoma Society.