Overexpression of parathyroid hormone-related protein or parathyroid hormone in transgenic mice impairs branching morphogenesis during mammary gland development

Development ◽  
1995 ◽  
Vol 121 (11) ◽  
pp. 3539-3547 ◽  
Author(s):  
J.J. Wysolmerski ◽  
J.F. McCaughern-Carucci ◽  
A.G. Daifotis ◽  
A.E. Broadus ◽  
W.M. Philbrick
Keyword(s):  
Parathyroid Hormone ◽  
Transgenic Mice ◽  
Branching Morphogenesis ◽  
Mammary Glands ◽  
Myoepithelial Cells ◽  
Breast Development ◽  
Related Protein ◽  
Amino Terminal ◽  
Parathyroid Hormone Related Protein ◽  
Breast Hypoplasia

Parathyroid hormone-related protein (PTHrP) was originally discovered as the tumor product that causes humoral hypercalcemia of malignancy. PTHrP is now known to be widely expressed in many normal fetal tissues where it may participate in the regulation of organogenesis. In this report, we document that overexpression of PTHrP in myoepithelial cells in the mammary glands of transgenic mice resulted in a form of breast hypoplasia characterized by a profound defect in branching morphogenesis of the developing mammary duct system. In addition, transgenic mice manifested a defect in lobuloalveolar development during pregnancy that seemed to be, in part, the consequence of an impaired ability to form terminal ducts in response to estrogen and progesterone stimulation. The effects of PTHrP on branching morphogenesis during breast development appeared to be the result of amino-terminal PTH-like sequences that signal through the PTH/PTHrP receptor, since overexpression of parathyroid hormone itself in the mammary glands of transgenic mice caused a similar development phenotype, and delivery of PTHrP (1–36) via locally implanted slow-release pellets impaired breast development in normal mice. These results suggest that PTHrP, which is a native product of mammary epithelial and myoepithelial cells may participate in normal breast development, perhaps as a locally secreted growth inhibitor.

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.

Circulating levels of immunoreactive parathyroid hormone-related protein and intact parathyroid hormone in human fetuses and newborns

1996 ◽  
Vol 134 (4) ◽  
pp. 437-442 ◽  
Author(s):  
Nicholas E Papantoniou ◽  
Peter D Papapetrou ◽  
Aristidis J Antsaklis ◽  
Panayotis E Kontoleon ◽  
Spyros A Mesogitis ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Reproductive Age ◽  
Fetal Life ◽  
Intact Parathyroid Hormone ◽  
Human Fetuses ◽  
Related Protein ◽  
Amino Terminal ◽  
Parathyroid Hormone Related Protein ◽  
Circulating Levels ◽  
Immunoreactive Parathyroid Hormone

Papantoniou NE, Papapetrou PD, Antsaklis AJ, Kontoleon PE, Mesogitis SA, Aravantinos D. Circulating levels of immunoreactive parathyroid hormone-related protein and intact parathyroid hormone in human fetuses and newborns. Eur J Endocrinol 1996;134:437–42. ISSN 0804–4643 Undetectable or extremely low levels of circulating immunoreactive parathyroid hormone (PTH) have been reported in human newborns while PTH bioactivity was high. This prompted the hypothesis that the fetal calcemic hormone might be PTH-related protein. The purpose of this study was to measure circulating immunoreactive PTH-related protein in human fetuses and newborns in order to investigate this hypothesis. Parathyroid hormone-related protein (PTHrP(1–86)) and intact PTH were measured using two-site immunoradiometric assays in plasma obtained by cordocentesis from 23 fetuses (19–33 weeks of gestation), from 17 newborns at term (38–41 weeks), from their mothers and from 22 normal women of reproductive age. Plasma PTHrP was detectable in all but one of the fetuses and newborns and in all the mothers and the controls. The mean level was similar among fetuses (19–33 weeks) (0.43 ± 0.18 pmol/l), newborns (0.48 ±0.12), mothers (0.48 ±0.14) and normal controls (0.46 ± 0.09). Plasma PTH was found to be significantly higher in fetuses at midgestation (1.0 ± 0.99 pmol/l) than in the newborns (0.22 ± 0.21) (p < 0.0025); maternal PTH was significantly higher compared to fetal level at mid-gestation (2.1 ± 1.0, p < 0.01) as well as at term (2.69 ± 1.40, p < 0.001). In the control women PTH was 3.07 ± 1.25 pmol/l. These results showed that plasma amino-terminal PTHrP-(1–86)) is detectable during the second half of human fetal life and its level remains unchanged during this period of time, in contrast to changing levels of fetal plasma PTH. The relatively low PTHrP-(1–86) level that we found in the newborns is not responsible for the high PTH-like bioactivity found by some investigators in cord blood at term. Peter D Papapetrou, Second Division of Endocrinology, "Alexandra" Hospital, 80 Vas. Sofias & Lourou Streets, Athens 115 28, Greece

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

Rescue of the parathyroid hormone-related protein knockout mouse demonstrates that parathyroid hormone-related protein is essential for mammary gland development

Development ◽  
1998 ◽  
Vol 125 (7) ◽  
pp. 1285-1294 ◽  
Author(s):  
J.J. Wysolmerski ◽  
W.M. Philbrick ◽  
M.E. Dunbar ◽  
B. Lanske ◽  
H. Kronenberg ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Parathyroid Hormone ◽  
Epithelial Cells ◽  
Mammary Epithelial Cells ◽  
Branching Morphogenesis ◽  
Mammary Epithelial ◽  
Related Protein ◽  
Transgenic Expression ◽  
Parathyroid Hormone Related Protein ◽  
Pthrp Receptor

Parathyroid hormone-related protein (PTHrP) was originally discovered as a tumor product that causes humoral hypercalcemia of malignancy. PTHrP is now known to be widely expressed in normal tissues and growing evidence suggests that it is an important developmental regulatory molecule. We had previously reported that overexpression of PTHrP in the mammary glands of transgenic mice impaired branching morphogenesis during sexual maturity and early pregnancy. We now demonstrate that PTHrP plays a critical role in the epithelial-mesenchymal communications that guide the initial round of branching morphogenesis that occurs during the embryonic development of the mammary gland. We have rescued the PTHrP-knockout mice from neonatal death by transgenic expression of PTHrP targeted to chondrocytes. These rescued mice are devoid of mammary epithelial ducts. We show that disruption of the PTHrP gene leads to a failure of the initial round of branching growth that is responsible for transforming the mammary bud into the rudimentary mammary duct system. In the absence of PTHrP, the mammary epithelial cells degenerate and disappear. The ability of PTHrP to support embryonic mammary development is a function of amino-terminal PTHrP, acting via the PTH/PTHrP receptor, for ablation of the PTH/PTHrP receptor gene recapitulates the phenotype of PTHrP gene ablation. We have localized PTHrP expression to the embryonic mammary epithelial cells and PTH/PTHrP receptor expression to the mammary mesenchyme using in situ hybridization histochemistry. Finally, we have rescued mammary gland development in PTHrP-null animals by transgenic expression of PTHrP in embryonic mammary epithelial cells. We conclude that PTHrP is a critical epithelial signal received by the mammary mesenchyme and involved in supporting the initiation of branching morphogenesis.

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