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Key stages in mammary gland development. Secretory activation in the mammary gland: it's not just about milk protein synthesis!

Anderson SM, Rudolph MC, McManaman JL, Neville MC - Breast Cancer Res. (2007)

Bottom Line: Much of the research to date on mammary epithelial differentiation has focused upon expression of milk protein genes, providing a somewhat distorted view of alveolar differentiation and secretory activation.While expression of milk protein genes increases during pregnancy and at secretory activation, the genes whose expression is more tightly regulated at this transition are those that regulate lipid biosynthesis.The sterol regulatory element binding protein (SREBP) family of transcription factors is recognized as regulating fatty acid and cholesterol biosynthesis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, University of Colorado Health Sciences Center, East 17th Avenue, Aurora, CO 80045, USA. Steve.Anderson@uchsc.edu

ABSTRACT
The transition from pregnancy to lactation is a critical event in the survival of the newborn since all the nutrient requirements of the infant are provided by milk. While milk contains numerous components, including proteins, that aid in maintaining the health of the infant, lactose and milk fat represent the critical energy providing elements of milk. Much of the research to date on mammary epithelial differentiation has focused upon expression of milk protein genes, providing a somewhat distorted view of alveolar differentiation and secretory activation. While expression of milk protein genes increases during pregnancy and at secretory activation, the genes whose expression is more tightly regulated at this transition are those that regulate lipid biosynthesis. The sterol regulatory element binding protein (SREBP) family of transcription factors is recognized as regulating fatty acid and cholesterol biosynthesis. We propose that SREBP1 is a critical regulator of secretory activation with regard to lipid biosynthesis, in a manner that responds to diet, and that the serine/threonine protein kinase Akt influences this process, resulting in a highly efficient lipid synthetic organ that is able to support the nutritional needs of the newborn.

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The size and location of cytoplasmic lipid droplets (CLDs) changes upon secretory activation. Mammary glands were isolated from FVB mice on pregnancy (P) days (a) 12, (b) 16, and (c) 18, and (d) day 2 of lactation (L2). Tissues were fixed in neutral-buffered formalin, stained with anti-adipophilin (ADRP) antibody and Alexa Fluor 594 conjugated secondary antibody to outline the cytoplasmic lipid droplets (appearing in red), Alexa Fluor 488-conjugated wheat germ agglutinin to outline the luminal surface of the luminal space of the secretory alveoli (appearing in green), and 4',6-diamino-2-phenylindole (DAPI) to stain the nuclei of mammary epithelial cells (appearing in blue). Idealized schematic drawings, not meant to represent the micrographs shown in the top panel, illustrate the positions of the luminal space (labeled LU), nuclei (purple), and CLDs (labeled red) at pregnancy days (e) 12, (f) 16, and (g) 18, and (h) day 2 of lactation. The scale bars in (a-d) represent 10 μm. Luminal space is indicated by the letters 'Lu', and the white arrowheads indicate CLDs.
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Figure 2: The size and location of cytoplasmic lipid droplets (CLDs) changes upon secretory activation. Mammary glands were isolated from FVB mice on pregnancy (P) days (a) 12, (b) 16, and (c) 18, and (d) day 2 of lactation (L2). Tissues were fixed in neutral-buffered formalin, stained with anti-adipophilin (ADRP) antibody and Alexa Fluor 594 conjugated secondary antibody to outline the cytoplasmic lipid droplets (appearing in red), Alexa Fluor 488-conjugated wheat germ agglutinin to outline the luminal surface of the luminal space of the secretory alveoli (appearing in green), and 4',6-diamino-2-phenylindole (DAPI) to stain the nuclei of mammary epithelial cells (appearing in blue). Idealized schematic drawings, not meant to represent the micrographs shown in the top panel, illustrate the positions of the luminal space (labeled LU), nuclei (purple), and CLDs (labeled red) at pregnancy days (e) 12, (f) 16, and (g) 18, and (h) day 2 of lactation. The scale bars in (a-d) represent 10 μm. Luminal space is indicated by the letters 'Lu', and the white arrowheads indicate CLDs.

Mentions: Perhaps the most obvious histological change marking the transition from pregnancy to lactation is the change in the size and cellular distribution of lipid droplets. At mid-pregnancy, small lipid droplets, referred to as cytoplasmic lipid droplets (CLDs), can be seen within luminal mammary epithelial cells. While these are readily apparent in standard histological sections stained with hematoxylin and eosin, we have found that they are better appreciated in sections that are stained with an antibody to adipophilin, which is found at the periphery of all lipid droplets within the alveolar cells (red stain in Figure 2) where DAPI (blue stain in Figure 2) has been used to stain the nuclei, and wheat germ agglutinin (green stain in Figure 2) to identify the luminal surface of the lobuloalveolar complexes (Figure 2). By the end of pregnancy the CLDs have increased dramatically in size (Figure 2c,g). Following parturition, CLDs are smaller and localized to the apical surface of the alveolar epithelial cells (Figure 2d,h). It is interesting to note that in many genetically engineered mice that exhibit lactation failure, large CLDs remain after parturition and can be observed on the first and sometimes even the second day of lactation. In particular, we have characterized lactation failure in transgenic mice that express activated myr-Akt1 in the mammary gland [25]; prominent CLDs are apparent following parturition, suggesting that secretory activation has not occurred. The presence of large CDLs post-partum is also noted in the following genetically engineered mice: Src mice (MM Richert and SM Anderson, unpublished data); WAP-human protein C [26]; bovine oxytocin transgenic [27]; oxytocin knockout mice [28]; α-lactalbumin knockout mice [29]; butyrophilin knockout mice [30]; and the xanthine oxidoreductase heterozygous knockout mice [31].


Key stages in mammary gland development. Secretory activation in the mammary gland: it's not just about milk protein synthesis!

Anderson SM, Rudolph MC, McManaman JL, Neville MC - Breast Cancer Res. (2007)

The size and location of cytoplasmic lipid droplets (CLDs) changes upon secretory activation. Mammary glands were isolated from FVB mice on pregnancy (P) days (a) 12, (b) 16, and (c) 18, and (d) day 2 of lactation (L2). Tissues were fixed in neutral-buffered formalin, stained with anti-adipophilin (ADRP) antibody and Alexa Fluor 594 conjugated secondary antibody to outline the cytoplasmic lipid droplets (appearing in red), Alexa Fluor 488-conjugated wheat germ agglutinin to outline the luminal surface of the luminal space of the secretory alveoli (appearing in green), and 4',6-diamino-2-phenylindole (DAPI) to stain the nuclei of mammary epithelial cells (appearing in blue). Idealized schematic drawings, not meant to represent the micrographs shown in the top panel, illustrate the positions of the luminal space (labeled LU), nuclei (purple), and CLDs (labeled red) at pregnancy days (e) 12, (f) 16, and (g) 18, and (h) day 2 of lactation. The scale bars in (a-d) represent 10 μm. Luminal space is indicated by the letters 'Lu', and the white arrowheads indicate CLDs.
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Related In: Results  -  Collection

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Figure 2: The size and location of cytoplasmic lipid droplets (CLDs) changes upon secretory activation. Mammary glands were isolated from FVB mice on pregnancy (P) days (a) 12, (b) 16, and (c) 18, and (d) day 2 of lactation (L2). Tissues were fixed in neutral-buffered formalin, stained with anti-adipophilin (ADRP) antibody and Alexa Fluor 594 conjugated secondary antibody to outline the cytoplasmic lipid droplets (appearing in red), Alexa Fluor 488-conjugated wheat germ agglutinin to outline the luminal surface of the luminal space of the secretory alveoli (appearing in green), and 4',6-diamino-2-phenylindole (DAPI) to stain the nuclei of mammary epithelial cells (appearing in blue). Idealized schematic drawings, not meant to represent the micrographs shown in the top panel, illustrate the positions of the luminal space (labeled LU), nuclei (purple), and CLDs (labeled red) at pregnancy days (e) 12, (f) 16, and (g) 18, and (h) day 2 of lactation. The scale bars in (a-d) represent 10 μm. Luminal space is indicated by the letters 'Lu', and the white arrowheads indicate CLDs.
Mentions: Perhaps the most obvious histological change marking the transition from pregnancy to lactation is the change in the size and cellular distribution of lipid droplets. At mid-pregnancy, small lipid droplets, referred to as cytoplasmic lipid droplets (CLDs), can be seen within luminal mammary epithelial cells. While these are readily apparent in standard histological sections stained with hematoxylin and eosin, we have found that they are better appreciated in sections that are stained with an antibody to adipophilin, which is found at the periphery of all lipid droplets within the alveolar cells (red stain in Figure 2) where DAPI (blue stain in Figure 2) has been used to stain the nuclei, and wheat germ agglutinin (green stain in Figure 2) to identify the luminal surface of the lobuloalveolar complexes (Figure 2). By the end of pregnancy the CLDs have increased dramatically in size (Figure 2c,g). Following parturition, CLDs are smaller and localized to the apical surface of the alveolar epithelial cells (Figure 2d,h). It is interesting to note that in many genetically engineered mice that exhibit lactation failure, large CLDs remain after parturition and can be observed on the first and sometimes even the second day of lactation. In particular, we have characterized lactation failure in transgenic mice that express activated myr-Akt1 in the mammary gland [25]; prominent CLDs are apparent following parturition, suggesting that secretory activation has not occurred. The presence of large CDLs post-partum is also noted in the following genetically engineered mice: Src mice (MM Richert and SM Anderson, unpublished data); WAP-human protein C [26]; bovine oxytocin transgenic [27]; oxytocin knockout mice [28]; α-lactalbumin knockout mice [29]; butyrophilin knockout mice [30]; and the xanthine oxidoreductase heterozygous knockout mice [31].

Bottom Line: Much of the research to date on mammary epithelial differentiation has focused upon expression of milk protein genes, providing a somewhat distorted view of alveolar differentiation and secretory activation.While expression of milk protein genes increases during pregnancy and at secretory activation, the genes whose expression is more tightly regulated at this transition are those that regulate lipid biosynthesis.The sterol regulatory element binding protein (SREBP) family of transcription factors is recognized as regulating fatty acid and cholesterol biosynthesis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, University of Colorado Health Sciences Center, East 17th Avenue, Aurora, CO 80045, USA. Steve.Anderson@uchsc.edu

ABSTRACT
The transition from pregnancy to lactation is a critical event in the survival of the newborn since all the nutrient requirements of the infant are provided by milk. While milk contains numerous components, including proteins, that aid in maintaining the health of the infant, lactose and milk fat represent the critical energy providing elements of milk. Much of the research to date on mammary epithelial differentiation has focused upon expression of milk protein genes, providing a somewhat distorted view of alveolar differentiation and secretory activation. While expression of milk protein genes increases during pregnancy and at secretory activation, the genes whose expression is more tightly regulated at this transition are those that regulate lipid biosynthesis. The sterol regulatory element binding protein (SREBP) family of transcription factors is recognized as regulating fatty acid and cholesterol biosynthesis. We propose that SREBP1 is a critical regulator of secretory activation with regard to lipid biosynthesis, in a manner that responds to diet, and that the serine/threonine protein kinase Akt influences this process, resulting in a highly efficient lipid synthetic organ that is able to support the nutritional needs of the newborn.

Show MeSH
Related in: MedlinePlus