Parathyroid hormone-related protein signaling is necessary for sexual dimorphism during embryonic mammary development

Development ◽  
1999 ◽  
Vol 126 (16) ◽  
pp. 3485-3493
Author(s):  
M.E. Dunbar ◽  
P.R. Dann ◽  
G.W. Robinson ◽  
L. Hennighausen ◽  
J.P. Zhang ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Cell Fate ◽  
Ectopic Expression ◽  
Mammary Development ◽  
Mammary Epithelial ◽  
Related Protein ◽  
Cell Fate Decisions ◽  
Parathyroid Hormone Related Protein ◽  
Pthrp Expression ◽  
Mammary Mesenchyme

Male mice lack mammary glands due to the interaction of circulating androgens with local epithelial-mesenchymal signaling in the developing mammary bud. Mammary epithelial cells induce androgen receptor (AR) within the mammary mesenchyme and, in response to androgens, the mesenchyme condenses around the epithelial bud, destroying it. We show that this process involves apoptosis and that, in the absence of parathyroid hormone-related protein (PTHrP) or its receptor, the PTH/PTHrP receptor (PPR1), it fails due to a lack of mesenchymal AR expression. In addition, the expression of tenascin C, another marker of the mammary mesenchyme, is also dependent on PTHrP. PTHrP expression is initiated on E11 and, within the ventral epidermis, is restricted to the forming mammary epithelial bud. In contrast, PPR1 expression is not limited to the mammary bud, but is found generally within the subepidermal mesenchyme. Finally, transgenic overexpression of PTHrP within the basal epidermis induces AR and tenasin C expression within the ventral dermis, suggesting that ectopic expression of PTHrP can induce the ventral mesenchyme to express mammary mesenchyme markers. We propose that PTHrP expression specifically within the developing epithelial bud acts as a dominant signal participating in cell fate decisions leading to a specialized mammary mesenchyme.

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.

Parathyroid hormone-related protein increases cAMP production in mammary epithelial cells

1993 ◽  
Vol 264 (3) ◽  
pp. E471-E475 ◽  
Author(s):  
S. Ferrari ◽  
R. Rizzoli ◽  
C. Chaponnier ◽  
G. Gabbiani ◽  
J. P. Bonjour
Keyword(s):  
Parathyroid Hormone ◽  
Epithelial Cells ◽  
Breast Tissue ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Immunofluorescent Staining ◽  
Regulatory Function ◽  
Related Protein ◽  
Camp Production ◽  
Parathyroid Hormone Related Protein

Parathyroid hormone-related protein (PTHrP) is a major cause of malignant hypercalcemia but has been found in many nontumoral tissues as well. Thus it is produced by the mammary gland during lactation and released into milk. Whether PTHrP directly affects breast tissue is however not known. We investigated the effects of PTHrP on adenosine 3',5'-cyclic monophosphate (cAMP) production in primary cultures of mammary epithelial cells isolated from lactating rats. On the 7th day in culture, synthetic PTHrP-(1-34), recombinant (r) PTHrP-(1-108), and rPTHrP-(1-141) stimulated cAMP production in a concentration-dependent manner. Thus PTHrP-(1-34) induced a 1.92 +/- 0.04-fold stimulation of cAMP production (mean +/- SE, n = 5 separate experiments, P < 0.001). At the time of maximal responsiveness to PTHrP, a significant proportion of the cells was characterized by an elongated shape and a positive immunofluorescent staining for both prekeratin and alpha-smooth muscle actin 1, compatible with a myoepithelial phenotype. It therefore appears that PTHrP can stimulate the production of cAMP in mammary cells, suggesting a possible autocrine/paracrine regulatory function for PTHrP in breast tissue.

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.

Dexamethasone regulation of parathyroid hormone-related protein (PTHrP) expression in a squamous cancer cell line

1994 ◽  
Vol 101 (1-2) ◽  
pp. 295-306 ◽  
Author(s):  
Jane A. Glatz ◽  
Joan K. Heath ◽  
Justine Southby ◽  
Leonie M. O'Keeffe ◽  
Kiriyama Takeshi ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Cell Line ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Related Protein ◽  
Parathyroid Hormone Related Protein ◽  
Squamous Cancer ◽  
Pthrp Expression

Parathyroid hormone-related protein induction in focal stroke: a neuroprotective vascular peptide

2003 ◽  
Vol 284 (4) ◽  
pp. R1021-R1030 ◽  
Author(s):  
Janet L. Funk ◽  
Elton Migliati ◽  
Guanjie Chen ◽  
Hongbing Wei ◽  
Jonathan Wilson ◽  
...  
Keyword(s):  
Blood Flow ◽  
Parathyroid Hormone ◽  
Cell Injury ◽  
Tissue Injury ◽  
Northern Analysis ◽  
Related Protein ◽  
Cerebral Microvessels ◽  
Ischemic Brain ◽  
Parathyroid Hormone Related Protein ◽  
Pthrp Expression

Parathyroid hormone-related protein (PTHrP) is a multifunctional peptide that enhances blood flow in non-central nervous system (CNS) vascular beds by causing vasodilation. PTHrP expression is induced in non-CNS organs in response to ischemia. Experiments were therefore undertaken to determine whether PTHrP can be induced in brain in response to ischemic injury and whether PTHrP can act locally as a vasodilator in the cerebral vasculature, an effect that could be neuroprotective in the setting of stroke. PTHrP expression was examined by Northern analysis and immunohistochemical staining in male Sprague-Dawley rats subjected to permanent middle cerebral artery occlusion (MCAO). Vasodilatory effects of superfused PTHrP(1–34) on pial arterioles were determined by intravital fluorescence microscopy. Effects of PTHrP(1–34) peptide administration on MCAO infarction size reduction were assessed. PTHrP expression was induced in the ischemic hemisphere as early as 4 h after MCAO and remained elevated for up to 24 h. Increased immunoreactive PTHrP at sites of ischemic tissue injury was located in the cerebral microvessels. Superfusion with PTHrP(1–34) peptide for up to 25 min increased pial arteriolar diameter by 30% in normal animals. In animals with permanent MCAO, PTHrP(1–34) peptide treatment significantly decreased cortical infarct size (−47%). In summary, PTHrP expression increases at sites of ischemic brain injury in the cerebrovasculature. This local increase in PTHrP could be an adaptive response that enhances blood flow to the ischemic brain, thus limiting cell injury.

scholarly journals Parathyroid hormone-related protein activates Wnt signaling to specify the embryonic mammary mesenchyme

Development ◽  
2012 ◽  
Vol 139 (22) ◽  
pp. 4239-4249 ◽  
Author(s):  
M. Hiremath ◽  
P. Dann ◽  
J. Fischer ◽  
D. Butterworth ◽  
K. Boras-Granic ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Wnt Signaling ◽  
Related Protein ◽  
Parathyroid Hormone Related Protein ◽  
Mammary Mesenchyme

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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