Abstract
In order to gain a better understanding of the molecular processes that underlie apoptosis and tissue regression in mammary gland, we undertook a large-scale analysis of transcriptional changes during the mouse mammary pregnancy cycle, with emphasis on the transition from lactation to involution. Affymetrix microarrays, representing 8618 genes, were used to compare mammary tissue from 12 time points (one virgin, three gestation, three lactation and five involution stages). Six animals were used for each time point. Common patterns of gene expression across all time points were identified and related to biological function. The majority of significantly induced genes in involution were also differentially regulated at earlier stages in the pregnancy cycle. This included a marked increase in inflammatory mediators during involution and at parturition, which correlated with leukaemia inhibitory factor-Stat3 (signal transducer and activator of signalling-3) signalling. Before involution, expected increases in cell proliferation, biosynthesis and metabolism-related genes were observed. During involution, the first 24 hours after weaning was characterized by a transient increase in expression of components of the death receptor pathways of apoptosis, inflammatory cytokines and acute phase response genes. After 24 hours, regulators of intrinsic apoptosis were induced in conjunction with markers of phagocyte activity, matrix proteases, suppressors of neutrophils and soluble components of specific and innate immunity. We provide a resource of mouse mammary gene expression data for download or online analysis. Here we highlight the sequential induction of distinct apoptosis pathways in involution and the stimulation of immunomodulatory signals, which probably suppress the potentially damaging effects of a cellular inflammatory response while maintaining an appropriate antimicrobial and phagocytic environment.
Highlights
In order to gain a better understanding of the molecular processes that underlie apoptosis and tissue regression in mammary gland, we undertook a large-scale analysis of transcriptional changes during the mouse mammary pregnancy cycle, with emphasis on the transition from lactation to involution
The first 24 hours after weaning was characterized by a transient increase in expression of components of the death receptor pathways of apoptosis, inflammatory cytokines and acute phase response genes
We focused our analysis on the changes in gene expression that occur during the first 4 days of postlactational regression, harvesting at five time points during this period
Summary
In order to gain a better understanding of the molecular processes that underlie apoptosis and tissue regression in mammary gland, we undertook a large-scale analysis of transcriptional changes during the mouse mammary pregnancy cycle, with emphasis on the transition from lactation to involution. Mammary gland development during the pregnancy cycle is characterized by successive phases of cell growth, differentiation, high metabolic activity and apoptosis. At the ultrastructural level this includes dramatic changes in tissue architecture, involving ductal epithelial branching and morphogenesis, invasion of tissue compartments, vascularization and subsequent organized remodelling. These events are highly reproducible and strictly controlled at the transcriptional level by circulating hormones and locally derived factors [1]. CAM = cell adhesion molecule; C/ebp = CAAT-enhancer binding protein; IGF = insulin-like growth factor; IL = interleukin; LIF = leukaemia R92 inhibitory factor; LPS = lipopolysaccharide; NF-κB = nuclear factor-κB; Stat = signal transducer and activator of transcription
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