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STAT5 deletion in macrophages alters ductal elongation and branching during mammary gland development.

ABSTRACT: Macrophages are required for proper mammary gland development and maintaining tissue homeostasis. However, the mechanisms by which macrophages regulate this process remain unclear. Here, we identify STAT5 as an important regulator of macrophage function in the developing mammary gland. Analysis of mammary glands from mice with STAT5-deficient macrophages demonstrates delayed ductal elongation, enhanced ductal branching and increased epithelial proliferation. Further analysis reveals that STAT5 deletion in macrophages leads to enhanced expression of proliferative factors such as Cyp19a1/aromatase and IL-6. Mechanistic studies demonstrate that STAT5 binds directly to the Cyp19a1 promoter in macrophages to suppress gene expression and that loss of STAT5 results in enhanced stromal expression of aromatase. Finally, we demonstrate that STAT5 deletion in macrophages cooperates with oncogenic initiation in mammary epithelium to accelerate the formation of estrogen receptor (ER)-positive hyperplasias. These studies establish the importance of STAT5 in macrophages during ductal morphogenesis in the mammary gland and demonstrate that altering STAT5 function in macrophages can affect the development of tissue-specific disease.

SUBMITTER: Brady NJ

PROVIDER: S-EPMC5621646 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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STAT5 deletion in macrophages alters ductal elongation and branching during mammary gland development.

Brady Nicholas J NJ Farrar Michael A MA Schwertfeger Kathryn L KL

Developmental biology 20170609 1

Macrophages are required for proper mammary gland development and maintaining tissue homeostasis. However, the mechanisms by which macrophages regulate this process remain unclear. Here, we identify STAT5 as an important regulator of macrophage function in the developing mammary gland. Analysis of mammary glands from mice with STAT5-deficient macrophages demonstrates delayed ductal elongation, enhanced ductal branching and increased epithelial proliferation. Further analysis reveals that STAT5 d ...[more]

PMID: 28606561

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Project description:In the mammary gland, genetic circuits controlled by estrogen, progesterone, and prolactin, act in concert with pathways regulated by members of the epidermal growth factor family to orchestrate growth and morphogenesis during puberty, pregnancy and lactation. However, the precise mechanisms underlying the crosstalk between the hormonal and growth factor pathways remain poorly understood. We have identified the CUB and zona pellucida-like domain-containing protein 1 (CUZD1), expressed in mammary ductal and alveolar epithelium, as a novel mediator of mammary gland proliferation and differentiation during pregnancy and lactation. Cuzd1-null mice exhibited a striking impairment in mammary ductal branching and alveolar development during pregnancy, resulting in a subsequent defect in lactation. Gene expression profiling of mammary epithelium revealed that CUZD1 regulates the expression of a subset of the EGF family growth factors, epiregulin, neuregulin-1, and epigen, which act in an autocrine fashion to activate ErbB1 and ErbB4 receptors. Proteomic studies further revealed that CUZD1 interacts with a complex containing JAK1/JAK2 and STAT5, downstream transducers of prolactin signaling in the mammary gland. In the absence of CUZD1, STAT5 phosphorylation in the mammary epithelium during alveologenesis was abolished. Conversely, elevated expression of Cuzd1 in mammary epithelial cells stimulated prolactin-induced phosphorylation and nuclear translocation of STAT5. Chromatin immunoprecipitation confirmed co-occupancy of phosphorylated STAT5 and CUZD1 in the regulatory regions of epiregulin, a potential regulator of epithelial proliferation, and whey acidic protein, a marker of epithelial differentiation. Collectively, these findings suggest that CUZD1 plays a critical role in prolactin-induced JAK/STAT5 signaling that controls the expression of key STAT5 target genes involved in mammary epithelial proliferation and differentiation during alveolar development.

Dataset Information

STAT5 deletion in macrophages alters ductal elongation and branching during mammary gland development.

Publications

STAT5 deletion in macrophages alters ductal elongation and branching during mammary gland development.

Similar Datasets

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