Transcriptional changes underlying the secretory activation phase of mammary gland development.
Journal - Molecular endocrinology (Baltimore, Md.) (United States )
The secretory activation stage of mammary gland development occurs after parturition and converts inactive lobuloalveoli to active milk secretion. This process is triggered by progestin withdrawal and depends upon augmented prolactin (Prl) signaling. Little is known about the Prl-induced transcriptional changes that occur in the mammary gland to drive this process. To examine changes in the mammary transcriptome responsible for secretory activation, we have used transcript profiling of three mouse models that exhibit failure of secretory activation: knockout of galanin (a regulator of pituitary Prl production and a mammary cell autonomous modulator of Prl action); treatment with S179D Prl (a phosphoprolactin mimic); and knockout of a single Prl receptor allele. A significant reduction in expression was observed in genes belonging to 46 gene ontologies including those representing milk proteins, metabolism, lipid, cholesterol and fatty acid biosynthetic enzymes, immune response, and key transcription factors. A set of 35 genes, commonly regulated in all three models, was identified and their role in lactogenesis was validated by examining their expression in response to Prl stimulation or signal transducer and activator of transcription 5 knockdown in the HC11 mouse mammary cell culture model. The transcript profiles provided by these experiments identify 35 key genes (many for the first time) involved in the secretory activation phase of mammary gland development, show that S179D acts as an antagonist of Prl action, and provide insight into the partial penetrance of failed lactation in Prl receptor heterozygous females.
|ISSN : ||0888-8809|
|Mesh Heading : ||Alleles Animals Cells, Cultured DNA-Binding Proteins Female Galanin Gene Expression Profiling Lactation Lipids Mammary Glands, Animal Mice Mice, Knockout Milk Proteins Mutation Oligonucleotide Array Sequence Analysis Phosphorylation Prolactin Protein Biosynthesis STAT5 Transcription Factor Trans-Activators antagonists & inhibitors genetics biosynthesis anatomy & histology secretion antagonists & inhibitors genetics metabolism pharmacology genetics antagonists & inhibitors|
|Mesh Heading Relevant : ||Transcription, Genetic metabolism genetics growth & development metabolism metabolism|
The neuropeptide galanin augments lobuloalveolar development.
Journal - The Journal of biological chemistry (United States )
Mammary lobuloalveolar development during pregnancy is controlled by ovarian sex steroids and pituitary prolactin release. In organ culture these hormones are incapable of reproducing the density and size of lobuloalveoli seen in mice, suggesting the existence of other undiscovered factors. We showed previously that galanin knockout mice fail to lactate sufficiently for pup survival following their first pregnancy. Here we demonstrate that prolactin treatment of galanin knockout mice allows pup survival but does not completely rescue lobuloalveolar development or reduced milk protein expression. When galanin was used in combination with prolactin in mammary organ culture, larger and more numerous lobules were produced than with prolactin alone. Galanin alone produced sustained activation of STAT5a and the induction of milk protein expression but did not induce lobulogenesis. Examination of the transcriptional interaction between galanin and prolactin using oligonucleotide microarrays demonstrated synergistic and antagonistic modes of interaction between these hormones. These data establish a new role for galanin as a hormone augmenting mammary development during pregnancy in concert with prolactin.
|ISSN : ||0021-9258|
|Mesh Heading : ||Animals Cell Differentiation DNA-Binding Proteins Drug Interactions Epithelial Cells Female Galanin Gene Expression Regulation Lactation Mammary Glands, Animal Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Milk Proteins Oligonucleotide Array Sequence Analysis Organ Culture Techniques Pregnancy Prolactin Reverse Transcriptase Polymerase Chain Reaction STAT5 Transcription Factor Trans-Activators Transcription, Genetic drug effects metabolism cytology deficiency genetics drug effects transplantation analysis biosynthesis pharmacology metabolism|
|Mesh Heading Relevant : ||pharmacology growth & development|