Generation and Validation of a Mouse Line with a Floxed SRC-3/AIB1 Allele for Conditional Knockout

<p>The steroid receptor coactivator-3 (SRC-3), also known as AIB1, ACTR, p/CIP and NCOA3, is a transcriptional coactivator for nuclear receptors and certain other transcription factors. SRC-3 is widely expressed and plays important physiological functions and pathogenic roles in breast and prostate cancers. <i>SRC-3</i> knockout (<i>SRC-3^-/-</i>) mice display genetic background-dependent embryonic lethality and multiple local and systemic abnormalities. Since both the partial lethality and the systemic effects caused by global <i>SRC-3</i> knockout interfere with downstream investigation of tissue-specific function of SRC-3, we have generated floxed <i>SRC-3</i> (<i>SRC-3^f/f</i>) mice with conditional alleles carrying loxP sites in introns 10 and 12 by a gene-targeting strategy. The two <i>SRC-3^f/f</i> mouse lines (A and B) are indistinguishable from wild type mice. To test if deletion of the floxed exons 11 and 12 for SRC-3 nuclear receptor interaction domains and disruption of its downstream sequence for transcriptional activation domains would inactivate <i>SRC-3</i> function, <i>SRC-3^f/f</i> mice were crossbred with <i>EIIa-Cre</i> mice to generate <i>SRC-3^d/d</i> mice with germ line deletion of the floxed <i>SRC-3</i> gene. Both lines of <i>SRC-3^d/d</i> mice exhibited growth retardation and low IGF-I levels, which was similar to that observed in <i>SRC-3^-/-</i> mice. The line A <i>SRC-3^d/d</i> mice showed normal viability, while line B <i>SRC-3^d/d</i> mice showed partial lethality similar to <i>SRC-3^-/-</i> mice, probably due to variable distributions of genetic background during breeding. These results demonstrate that the floxed <i>SRC-3</i> mouse lines have been successfully established. These mice will be useful for investigating the cell type- and developmental stage-specific functions of SRC-3.</p>