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Indirect Immunofluorescence on Frozen Sections of Mouse Mammary Gland
Published on: December 1, 2015
Cripto-1 ablation disrupts alveolar development in the mouse mammary gland through a progesterone receptor-mediated
Malgorzata Klauzinska1, David McCurdy2, Maria Cristina Rangel1
1Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland.
Abstract:
Cripto-1, a member of the epidermal growth factor-Cripto-1/FRL-1/Cryptic family, is critical for early embryonic development. Together with its ligand Nodal, Cripto-1 has been found to be associated with the undifferentiated status of mouse and human embryonic stem cells. Several studies have clearly shown that Cripto-1 is involved in regulating branching morphogenesis and epithelial-mesenchymal transition of the mammary gland both in vitro and in vivo and together with the cofactor GRP78 is critical for the maintenance of mammary stem cells ex vivo. Our previous studies showed that mammary-specific overexpression of human Cripto-1 exhibited dramatic morphological alterations in nulliparous mice mammary glands. The present study shows a novel mechanism for Cripto-1 regulation of mammary gland development through direct effects on progesterone receptor expression and pathways regulated by progesterone in the mammary gland. We demonstrate a strict temporal regulation of mouse Cripto-1 (mCripto-1) expression that occurs during mammary gland development and a stage-specific function of mCripto-1 signaling during mammary gland development. Our data suggest that Cripto-1, like the progesterone receptor, is not required for the initial ductal growth but is essential for subsequent side branching and alveologenesis during the initial stages of pregnancy. Dissection of the mechanism by which this occurs indicates that mCripto-1 activates receptor activator NF-κB/receptor activator NF-κB ligand, and NF-κB signaling pathways.
Insights
Cripto-1 is crucial for mammary gland development, regulating progesterone receptor expression and pathways. It is essential for side branching and alveologenesis during early pregnancy in mice.
Area of Science:
- Developmental Biology
- Stem Cell Biology
- Molecular Endocrinology
Background:
- Cripto-1, a key embryonic factor, influences stem cell pluripotency and mammary gland development.
- Previous studies linked Cripto-1 overexpression to mammary gland morphological changes.
- Cripto-1 interacts with GRP78 to maintain mammary stem cells.
Purpose of the Study:
- To elucidate the novel mechanism of Cripto-1 in mammary gland development.
- To investigate Cripto-1's direct effects on progesterone receptor expression.
- To understand the temporal and stage-specific functions of Cripto-1 signaling.
Main Methods:
- Temporal expression analysis of mouse Cripto-1 (mCripto-1) during mammary gland development.
- Investigation of mCripto-1's role in progesterone receptor pathways.
- Analysis of mCripto-1's impact on receptor activator NF-κB signaling.
Main Results:
- mCripto-1 expression is strictly regulated during mammary gland development.
- mCripto-1 is essential for side branching and alveologenesis, similar to progesterone receptor function.
- mCripto-1 signaling activates receptor activator NF-κB/receptor activator NF-κB ligand pathways.
Conclusions:
- Cripto-1 plays a critical, stage-specific role in mammary gland development beyond initial ductal growth.
- Cripto-1 directly influences progesterone receptor expression and downstream signaling.
- The findings reveal a novel regulatory mechanism involving Cripto-1 in mammary stem cell function and tissue morphogenesis.
