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(American Journal of Pathology. 2001;158:1871-1880.)
© 2001 American Society for Investigative Pathology

Animal Models

Effects of in Vivo Heregulin ß1 Treatment in Wild-Type and ErbB Gene-Targeted Mice Depend on Receptor Levels and Pregnancy

Sue O’Shea^*, Kent Johnson, Ross Clark, Mark X. Sliwkowski and Sharon L. Erickson

From the Departments of Cell and Developmental Biology^*
and Pathology,
University of Michigan, Ann Arbor, Michigan; and the Departments of Endocrinology
and Molecular Oncology,
Genentech, Incorporated, South San Francisco, California

Mice heterozygous (+/-) for either heregulin (HRG), ErbB2, or ErbB3 were created by gene targeting, resulting in the loss of one functional gene copy and an associated decrease in targeted protein. We examined the in vivo activity of recombinant HRG peptide, rHRG ß1 (amino acids 177 to 241), in the three heterozygous mouse lines and in wild-type (WT) mice, both pregnant and nonpregnant. Nonpregnant WT and HRG(+/-) mice of both sexes were sensitive to rHRG ß1 treatment as evidenced by a high mortality rate associated with abdominal enlargement and parietal cell loss. However, pregnant WT mice and ErbB2 and ErbB3 heterozygous mice treated with rHRG ß1 were less affected, with significantly lower mortality rates and a less severe abdominal phenotype. Histological analysis revealed extensive breast ductal hyperplasia in females of all genotypes after rHRG ß1 treatment. Hyperplasia of other epithelial tissues such as the pancreas and intestine and the growth of cardiac nerve bundles were also observed, independent of sex.

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