scholarly journals Temporally regulated overexpression of parathyroid hormone-related protein in the mammary gland reveals distinct fetal and pubertal phenotypes

2001 ◽  
Vol 171 (3) ◽  
pp. 403-416 ◽  
Author(s):  
ME Dunbar ◽  
P Dann ◽  
CW Brown ◽  
J Van Houton ◽  
B Dreyer ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Parathyroid Hormone ◽  
Transgenic Mice ◽  
Mammary Development ◽  
Related Protein ◽  
Parathyroid Hormone Related Protein ◽  
Epithelial Cell Apoptosis ◽  
Ductal Elongation ◽  
Ductal Branching ◽  
Lobuloalveolar Development

We have previously demonstrated that overexpression of parathyroid hormone-related protein (PTHrP) in the mammary glands of transgenic mice results in defects in ductal elongation and branching during puberty and in lobuloalveolar development during pregnancy. In addition, we have shown that PTHrP is necessary for the formation of the initial ductal tree during embryonic mammary development. In order to examine the effect of varying the timing of PTHrP overexpression on mammary development, we created tetracycline-regulated, K14-tTA/Tet(O)-PTHrP double transgenic mice. In this report, we document that this 'tet-off' system directs transgene expression to the mammary gland and that it is fully repressed in the presence of tetracycline. Using these mice, we demonstrate that transient overexpression of PTHrP before birth causes defects in ductal branching during puberty and that overexpression of PTHrP during puberty decreases the rate of ductal elongation. Furthermore, we demonstrate that if PTHrP overexpression is initiated after ductal morphogenesis is completed, lobuloalveolar development is unaffected. Finally, we demonstrate that the impairment in ductal elongation caused by PTHrP is associated with an increase in the basal rate of epithelial cell apoptosis in terminal end buds and a failure to increase end bud cell proliferation and decrease apoptosis in response to estrogen and progesterone.

Cortisol, parathyroid hormone-related protein and the onset of calcium secretion by the mammary gland of the goat

1997 ◽  
Vol 64 (4) ◽  
pp. 633-636
Author(s):  
GORDON E. THOMPSON ◽  
S. KHAWAR ABBAS ◽  
CARL HOLT ◽  
ANTHONY D. CARE
Keyword(s):  
Mammary Gland ◽  
Parathyroid Hormone ◽  
Epithelial Cells ◽  
Tight Junctions ◽  
Calcium Transport ◽  
Extracellular Fluid ◽  
Secretory Cells ◽  
Related Protein ◽  
Parathyroid Hormone Related Protein ◽  
Calcium Secretion

During lactogenesis in the goat, the onset of secretion of calcium into milk occurs at parturition (Thompson et al. 1995) at approximately the same time as the onset of secretion of parathyroid hormone-related protein (PTHrP) by the mammary gland (Ratcliffe et al. 1992); these events may be unrelated or PTHrP may be involved in calcium transport from blood to milk.Parturition in goats is initiated by fetal secretion of cortisol (Flint et al. 1978) and maternal secretion of cortisol also increases (Paterson & Linzell, 1971). Injecting cortisol locally into the sinus of a mammary gland of the late-pregnant goat when the tight junctions between secretory epithelial cells appear to be ‘loose’, and injectate can reach the basolateral surfaces of secretory cells, stimulates an early tightening of these junctions (Thompson, 1996) as occurs naturally at parturition. This tightening can be produced by an increased concentration of ionized calcium in the extracellular fluid of the gland (Neville & Peaker, 1981).The experiments reported here were undertaken to determine if cortisol injection stimulates the mammary gland to secrete both PTHrP and calcium before parturition.

scholarly journals Cloning of bovine parathyroid hormone-related protein (PTHrP) cDNA and expression of PTHrP mRNA in the bovine mammary gland

1998 ◽  
Vol 20 (2) ◽  
pp. 271-280 ◽  
Author(s):  
SF Wojcik ◽  
FL Schanbacher ◽  
LK McCauley ◽  
H Zhou ◽  
V Kartsogiannis ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Parathyroid Hormone ◽  
Cdna Library ◽  
Bovine Milk ◽  
Bovine Brain ◽  
Molecular Heterogeneity ◽  
Related Protein ◽  
Parathyroid Hormone Related Protein ◽  
Lactating Mammary Gland ◽  
Brain Cdna Library

Parathyroid hormone-related protein (PTHrP) produced by the mammary gland has been postulated to have multiple functions in both the mother and neonate. In humans, alternative 3'-mRNA splicing and endoproteolytic processing result in multiple bioactive PTHrP peptides. Multiple PTHrP peptides also have been reported in bovine milk. To investigate the source of molecular heterogeneity of PTHrP in bovine milk, bovine PTHrP was cloned from a bovine brain cDNA library, sequenced and used to characterize the mammary PTHrP transcript. A 1065 bp clone (bP1) for bovine PTHrP was isolated from a brain cDNA library. The bP1 clone contained the entire coding sequence of PTHrP and 61 and 473 nucleotides of the 5'- and 3'-untranslated regions (UTRs) respectively. The predicted amino acid sequence of bovine PTHrP was 72-92% homologous to the sequences of chicken, rat, mouse, human, and canine PTHrP with the highest sequence divergence present in the C-terminal region of the peptide. The 5'- and 3'-UTRs of bovine brain PTHrP have a high degree of homology to exons 4 and 9 of human PTHrP respectively. PTHrP was expressed as a single 1200 nucleotide mRNA transcript in lactating bovine mammary tissue. RT-PCR using region-specific oligonucleotide primers derived from bP1 demonstrated that PTHrP mRNA transcripts in bovine brain and lactating mammary gland utilize the same 5'- and 3'-UTRs. Expression of PTHrP mRNA was localized to secretory and ductular epithelial cells within the lactating mammary gland, as detected using in situ hybridization. Expression of PTHrP mRNA was demonstrated in the mammary gland during late pregnancy and throughout lactation in cows.

Parathyroid hormone-related protein maintains mammary epithelial fate and triggers nipple skin differentiation during embryonic breast development

Development ◽  
2001 ◽  
Vol 128 (4) ◽  
pp. 513-525 ◽  
Author(s):  
J. Foley ◽  
P. Dann ◽  
J. Hong ◽  
J. Cosgrove ◽  
B. Dreyer ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Epithelial Cells ◽  
Cell Fate ◽  
Mesenchymal Cells ◽  
Mammary Development ◽  
Mammary Epithelial ◽  
Related Protein ◽  
Parathyroid Hormone Related Protein ◽  
Mammary Mesenchyme ◽  
Pthrp Receptor

Prior reports have demonstrated that both parathyroid hormone-related protein (PTHrP) and the type I PTH/PTHrP receptor are necessary for the proper development of the embryonic mammary gland in mice. Using a combination of loss-of-function and gain-of-function models, we now report that PTHrP regulates a series of cell fate decisions that are central to the survival and morphogenesis of the mammary epithelium and the formation of the nipple. PTHrP is made in the epithelial cells of the mammary bud and, during embryonic mammary development, it interacts with the surrounding mesenchymal cells to induce the formation of the dense mammary mesenchyme. In response, these mammary-specific mesenchymal cells support the maintenance of mammary epithelial cell fate, trigger epithelial morphogenesis and induce the overlying epidermis to form the nipple. In the absence of PTHrP signaling, the mammary epithelial cells revert to an epidermal fate, no mammary ducts are formed and the nipple does not form. In the presence of diffuse epidermal PTHrP signaling, the ventral dermis is transformed into mammary mesenchyme and the entire ventral epidermis becomes nipple skin. These alterations in cell fate require that PTHrP be expressed during development and they require the presence of the PTH/PTHrP receptor. Finally, PTHrP signaling regulates the epidermal and mesenchymal expression of LEF1 and (β)-catenin, suggesting that these changes in cell fate involve an interaction between the PTHrP and Wnt signaling pathways.

scholarly journals Overexpression of Parathyroid Hormone-related Protein in the Pancreatic Islets of Transgenic Mice Causes Islet Hyperplasia, Hyperinsulinemia, and Hypoglycemia

1996 ◽  
Vol 271 (2) ◽  
pp. 1200-1208 ◽  
Author(s):  
Rupangi C. Vasavada ◽  
Christi Cavaliere ◽  
A. Joseph D'Ercole ◽  
Pamela Dann ◽  
William J. Burtis ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Transgenic Mice ◽  
Pancreatic Islets ◽  
Related Protein ◽  
Parathyroid Hormone Related Protein ◽  
Islet Hyperplasia
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