Abstract
BackgroundMMTV-Cre mouse lines have played important roles in our understanding about the functions of numerous genes in mouse mammary epithelial cells during mammary gland development and tumorigenesis. However, numerous studies have not included MMTV-Cre mice as controls, and many investigators have not indicated which of the different MMTV-Cre founder lines were used in their studies. Here, we describe a lactation defect that severely limits the use of one of the most commonly used MMTV-Cre founder lines.Methodology/Principal FindingsTo explore the role of protein tyrosine phosphatase Shp1 in mammary gland development, mice bearing the floxed Shp1 gene were crossed with MMTV-Cre mice and mammary gland development was examined by histological and biochemical techniques, while lactation competency was assessed by monitoring pup growth. Surprisingly, both the Shp1fl/+;MMTV-Cre and MMTV-Cre female mice displayed a severe lactation defect when compared to the Shp1 fl/+ control mice. Histological and biochemical analyses reveal that female mice expressing the MMTV-Cre transgene, either alone or in combination with floxed genes, exhibit defects in lobuloalveolar expansion, presence of large cytoplasmic lipid droplets in luminal alveolar epithelial cells postpartum, and precocious induction of involution. Using a PCR-based genotyping method, the three different founder lines can be distinguished, and we determined that the MMTV-Cre line A, the most widely used MMTV-Cre founder line, exhibits a profound lactation defect that limits its use in studies on mammary gland development.Conclusions/SignificanceThe identification of a lactation defect in the MMTV-Cre line A mice indicates that investigators must use MMTV-Cre alone mice as control in studies that utilize Cre recombinase to excise genes of interest from mammary epithelial cells. Our results also suggest that previous results obtained in studies using the MMTV-Cre line A line should be re-evaluated if the controls did not include mice expressing only Cre recombinase.
Highlights
The ability to excise specific genes in a tissue-specific manner has offered a great advance in our ability to determine the roles that specific genes play in development and diseases such as cancer at the level of the whole animal [1,2]
Analysis of the contribution of specific genes in mammary gland development and tumorigenesis has been aided by the use of tissue specific promoters to overexpress genes of interest in the mammary gland, and these promoter systems have been extended to the tissue-specific expression of Cre recombinase
None of the pups nursed by the SH2-domain containing protein tyrosine phosphatase1 (Shp1) fl/+;MMTVCre dams gained weight normally over the first ten days of lactation, and all of the pups in four of the five litters died by day eighteen of lactation (L18)
Summary
The ability to excise specific genes in a tissue-specific manner has offered a great advance in our ability to determine the roles that specific genes play in development and diseases such as cancer at the level of the whole animal [1,2]. The most recent development has been bicistronic constructs that express both the Neu oncogene and Cre recombinase, MMTV-NIC, which allows for excision of genes of interest in cells that express the Neu oncogene [10] Each of these promoter systems has distinct advantages with regard to tissue-specificity and the temporal pattern of expression, the MMTV-Cre mice, those developed by the Hennighausen laboratory [5,6], have been perhaps the most extensively used Cre-expressing transgenic mouse lines with regard to the mammary gland. MMTV-Cre mouse lines have played important roles in our understanding about the functions of numerous genes in mouse mammary epithelial cells during mammary gland development and tumorigenesis. We describe a lactation defect that severely limits the use of one of the most commonly used MMTV-Cre founder lines
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