International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)

Table of Contents * Complex Genetics * Developmental Genetics * Gene Annotation * Gene Discovery * Genome Sequencing * Functional Genomics * Mutagenesis * Presentations * Verne Chapman Memorial Lecture

DISRUPTION OF THE MOUSE CTCF GENE RESULTS IN EARLY PREIMPLANTATION LETHALITY

Galina N. Filippova
Fred Hutchinson Cancer Research Center
1100 Fairview Ave. N, C2-023
PO box 19024
Seattle, WA 98109 USA

Co-Authors: 1) Galina N.Filippova, 1) Sara Fagerlie, 1) James M. Moore,1) Kevin P. Foley, 2) Joanne Whitehead 1) Chris Kemp, 2) Rolf Ohlsson, 3) Victor Lobanenkov
Institutions: 1)Human Biology Division, Fred Hutchinson Cancer Research Center, 2)Department of Development and Genetics, Uppsala University, 3) National Institute of Allergy and Infectious Diseases, National Institutes of Health

The CTCF gene encodes an evolutionary conserved, 11 zinc finger (ZF) transcription factor that is involved in different aspects of gene regulation including promoter activation or repression, hormone-responsive gene silencing, methylation-dependent chromatin insulation and genomic imprinting. Somatic missense mutations within the CTCF 11ZF DNA-binding domain have been observed in breast, prostate and Wilms' tumors. These mutations selectively change rather than completely disrupt CTCF function. To study the role of CTCF in cancer and normal development we isolated the mouse CTCF gene and generated a null allele via homologous recombination in embryonic stem cells by deleting all coding exons of CTCF. Heterozygous mice were vital and showed 2-3 fold increase in tumor development in comparison to their wild type littermates. However, when intercrossing heterozygotes, homozygous CTCF mice were selectively absent from the offspring. Furthermore, we could not detect CTCF -/- embryos even at day 3.5 of the development. In vitro growth experiments with early preimplantation stage embryos obtained from heterozygous intercrosses did not reveal any CTCF -/- embryos either.

These results establish the essential role of the CTCF protein in mammals and in cellular viability and are consistent with the notion than only subtle CTCF mutations are found in tumors.