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.

Reference

Aarts
M. M.
,
Levy
D.
,
He
B.
,
Stregger
S.
,
Chen
T.
,
Richard
S.
,
Henderson
J. E.
(
1999
)
Parathyroid hormone-related protein interacts with RNA.
J. Biol. Chem
274
,
4832
4838
Behrens
J.
,
von Kries
J.
,
Kuhl
M.
,
Bruhn
L.
,
Wedlich
D.
,
Grosschedl
R.
,
Birchmeier
W.
(
1996
)
Functional interaction of-catenin with the transcription factor LEF-1.
Nature
382
,
638
642
Brisken
C.
,
Heineman
A.
,
Chavarria
T.
,
Elenbaas
B.
,
Tan
J.
,
Dey
S. K.
,
McMahon
J. A.
,
McMahon
A. P.
,
Weinberg
R. A.
(
2000
)
Essential function of Wnt-4 in mammary gland development downstream of progesterone signaling.
Genes Dev
14
,
650
654
Christiansen
J. H.
,
Dennis
C. L.
,
Wicking
C. A.
,
Monkley
S. J.
,
Wilkinson
D. G.
,
Wainwright
B. J.
(
1995
)
Murine Wnt-11 and Wnt-12 have temporally and spatially restricted expression patterns during embryonic development.
Mech. Dev
51
,
341
350
Cunha
G. R.
,
Young
P.
,
Christov
K.
,
Guzman
R.
,
Nandi
J.
,
Talamsutes
F.
,
Thorderson
G.
(
1995
)
Mammary phenotypic expression induced in epideraml cells by embryonic mammary mesenchyme.
Acta Anat
152
,
195
204
DasGupta
R.
,
Fuchs
E.
(
1999
)
Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation.
Development
126
,
4557
4568
Dillon
D. A.
,
Daquila
T.
,
Reynolds
A. B.
,
Fearon
E. R.
,
Rimm
D. L.
(
1998
)
The Expression Of P120ctn Protein In Breast Cancer Is Independent Of-and -Catenin and E-Cadherin.
Am. J. Pathol
152
,
75
82
Dunbar
M. E.
,
Dann
P. R.
,
Robinson
G.
,
Hennighausen
L.
,
Zhang
J. P.
,
Wysolmerski
J. J.
(
1999
)
Parathyroid hormone-related protein is necessary for sexual dimorphism during embryonic mammary development.
Development
126
,
3485
3493
Eastman
Q.
,
Grosschedl
R.
(
1999
)
Regulation of Lef/TCF transcription factors by Wnt and other signals.
Current Opinion Cell Biol
11
,
233
240
Foley
J.
,
Longely
B. J.
,
Wysolmerski
J. J.
,
Dreyer
B. E.
,
Broadus
A. E.
,
Philbrick
W. M.
(
1998
)
Regulation of epidermal differentiation by PTHrP: evidence from PTHrP-null and PTHrP-overexpressing mice.
J. Inv. Dermatol
111
,
1122
1128
Furth
P. A.
,
St Onge
L.
,
Boger
H.
,
Gruss
P.
,
Gossen
M.
,
Kistner
A.
,
Bujard
H.
,
Hennighausen
L.
(
1994
)
Temporal control of gene expression in transgenic mice by a tetracycline-responsive promoter.
Proc. Natl. Acad. Sci. USA
91
,
9302
9306
Gat
U.
,
DasGupta
R.
,
Degenstein
L.
,
Fuchs
E.
(
1998
)
De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin.
Cell
95
,
605
614
Henderson
J. E.
,
Amizuka
N.
,
Warshawsky
H.
,
Biasotto
D.
,
Lanske
B. M. K.
,
Goltzman
D.
,
Karaplis
A. C.
(
1995
)
Nucleolar localization of parathyroid hormone-related peptide enhances survival of chondrocytes under conditions that promote apoptotic cell death.
Mol. Cell. Biol
15
,
4064
4075
Hennighausen
L.
,
Robinson
G. W.
(
1998
)
Think globally, act locally: the making of a mouse mammary gland.
Genes Dev
12
,
449
455
Juppner
H.
,
Abou-Samra
A. B.
,
Freeman
M.
,
Kong
X. F.
,
Schipani
E.
,
Richards
J.
,
Kolakowski
L. F.
,
Hock
J.
,
Potts
J. T.
,
Kronenberg
H. M.
,
Segre
G. V.
(
1991
)
A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide.
Science
254
,
1024
1026
Kishimoto
J.
,
Burgeson
R. E.
,
Morgan
B. A.
(
2000
)
Wnt signaling maintains the hair-inducing activity of the dermal papilla.
Genes Dev
14
,
1181
1185
Kopan
R.
,
Fuchs
E.
(
1989
)
A new look at an old problem: keratins as tools to investigate determination morphogenesis and differentiation in skin.
Genes Dev
3
,
1
15
Kratochwil
K.
,
Dull
M.
,
Farinas
I.
,
Galceran
J.
,
Grosschedl
R.
(
1996
)
Lef1 expression is activated by BMP-4 and regulates inductive tissue interactions in tooth and hair development.
Genes Dev
10
,
1382
1394
Lam
M. H. C.
,
House
C. M.
,
Tiganis
T.
,
Mitchelhill
K. I.
,
Sarcevic
B.
,
Cures
A.
,
Ramsay
R.
,
Kemp
B. E.
,
Martin
T. J.
,
Gillespie
M. T.
(
1999
)
Phosphorylation at the cyclin-dependent kinases site (Thr85) of parathyroid hormone-related protein negatively regultes its nuclear localization.
J. Biol. Chem
274
,
18559
18566
Lanske
B.
,
Karaplis
A.
,
Lee
K.
,
Luz
A.
,
Vortkamp
A.
,
Pirro
A.
,
Karperien
M.
,
Defize
L.
,
Ho
C.
,
Mulligan
R.
, et al. 
(
1996
)
PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth.
Science
273
,
663
666
Lee
K.
,
Deeds
J. D.
,
Segre
G. V.
(
1995
)
Expression of parathyroid hormone-related peptide and its receptor messenger ribonucleic acids during fetal development of rats.
Endocrinology
136
,
453
463
Massfelder
T.
,
Dann
P.
,
Wu
T. L.
,
Vasavada
R.
,
Helwig
J. J.
,
Stewart
A. F.
(
1997
)
Opposing mitogenic and anti-mitogenic actions of parathyroid hormone-related protein in vascular smooth muscle cells: a critical role for nuclear targeting,.
Proc. Natl. Acad. Sci. USA
94
,
13630
13635
Montagna
W.
(
1970
)
Histology and cytochemistry of human skin. XXXV. The nipple and areola.
Br. J. Dermatol
83
,
2
13
Miller
J. R.
,
Moon
R. T.
(
1996
)
Signal transduction through b-catenin and specification of cell fate during embryogenesis.
Genes Dev
10
,
2527
2539
Orloff
J. J.
,
Kats
J.
,
Urena
P.
,
Schipani
E.
,
Vasavada
R. C.
,
Philbrick
W. M.
,
Behal
A.
,
Abou-Samra
A. B.
,
Segre
G. V.
,
Juppner
H.
(
1995
)
Further evidence for a novel receptor for amino-terminal PTHrP on keratinocytes and squamous carcinoma cell lines.
Endocrinology
136
,
3016
3023
Philbrick
W. M.
,
Wysolmerski
J. J.
,
Galbraith
S.
,
Orloff
J. J.
,
Yang
K. H.
,
Vasavada
R. C.
,
Weir
E. C.
,
Broadus
A. E.
,
Stewart
A. F.
(
1996
)
Defining the roles of parathyroid hormone-related protein in normal physiology.
Physiol. Rev
76
,
127
173
Philbrick
W. M.
,
Dreyer
B. E.
,
Nakchbandi
I. A.
,
Karaplis
A. C.
(
1998
)
Parathyroid hormone-related protein is required for tooth eruption.
Proc. Natl. Acad. Sci. USA
95
,
11846
11851
Rothnagel
J. A.
,
Seki
T.
,
Ogo
M.
,
Longley
M. A.
,
Wojcik
S. M.
,
Bundman
D. S.
,
Bickenbach
J. R.
,
Roop
D. R.
(
1999
)
The mouse keratin 6 isoforms are differentially expressed in the hair follicle, footpad, tongue and activated epidermis.
Differentiation
65
,
119
130
Schockett
P.
,
Difilippantonio
M.
,
Hellman
N.
,
Schatz
D. G.
(
1995
)
A modified tetracycline-regulated system provides autoregulatory, inducible gene expression in cultured cells and transgenic mice.
Proc. Natl. Acad. Sci. USA
92
,
6522
6526
Schockett
P. E.
,
Schatz
D.G.
(
1996
)
Diverse strategies for tetracycline-regulated inducible gene expression.
Proc. Natl. Acad. Sci. USA
93
,
5173
5176
Schweizer
J.
,
Baust
I.
(
1989
)
Winter H. Identification of murine type I keratin 9 (73 kDa). and its immunolocalization in neonatal and adult mouse foot sole epidermis.
Exp. Cell Res
184
,
193
206
Strewler
G.J.
(
2000
)
The physiology of parathyroid hormone-related protein.
New Engl. J. Med
342
,
177
185
Toyoshima
Y.
,
Ohsako
S.
,
Nagano
R.
,
Matsumoto
M.
,
Hidaka
S.
,
Nishinakagawa
H.
(
1998
)
Histological changes in mouse nipple tissue during the reproductive cycle.
J. Vet. Med. Sci
60
,
405
411
Uyttendaele
H.
,
Soriano
J. V.
,
Montesano
R.
,
Kitajewski
J.
(
1998
)
Notch 4 and Wnt-1 proteins function to regulate branching morphogenesis of mammary epithelial cells in an opposing fashion.
Dev. Biol
196
,
204
217
van Genderen
C.
,
Okamura
R. M.
,
Farinas
I.
,
Quo
R.
,
Parslow
T. G.
,
Bruhn
L.
,
Grosschedl
R.
(
1994
)
Development of several organs that require inductive epithelial-mesenchymal interactions is impaired in LEF-1-deficient mice.
Genes Dev
8
,
2691
2703
Vortkamp
A.
,
Lee
K.
,
Lanske
B.
,
Segre
G. V.
,
Kronenberg
H. M.
,
Tabin
C. J.
(
1996
)
Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein.
Science
273
,
613
622
Weir
E. C.
,
Philbrick
W. M.
,
Amling
M.
,
Neff
L. A.
,
Baron
R.
,
Broadus
A. E.
(
1996
)
Targeted overexpression of parathyroid hormone-related peptide in chondrocytes causes chondrodysplasia and delayed endochondral bone formation.
Proc. Natl. Acad. Sci. USA
93
,
10240
10245
Widelitz
R. B.
,
Jiang
T. X.
,
Lu
J.
,
Chuong
C. M.
(
2000
)
beta-catenin in epithelial morphogenesis: conversion of part of avian foot scales into feather buds with a mutated beta-catenin.
Dev. Biol
219
,
98
114
Wysolmerski
J. J.
,
Broadus
A. E.
,
Zhou
J.
,
Fuchs
E.
,
Milstone
L. M.
,
Philbrick
W. M.
(
1994
)
Overexpression of parathyroid hormone-related protein in the skin of transgenic mice interferes with hair follicle development.
Proc. Natl. Acad. Sci. USA
91
,
1133
1137
Wysolmerski
J. J.
,
McCaughern-Carucci
J. F.
,
Daifotis
A. G.
,
Broadus
A. E.
,
Philbrick
W. M.
(
1995
)
Overexpression of parathyroid hormone-related protein or parathyroid hormone in transgenic mice impairs branching morphogenesis during mammary gland development.
Development
121
,
3539
3547
Wysolmerski
J. J.
,
Stewart
A. F.
(
1998
)
The physiology of parathyroid hormone-related protein: an emerging role as a developmental factor.
Annu. Rev. Physiol
60
,
431
460
Wysolmerski
J. J.
,
Philbrick
W. M.
,
Dunbar
M. E.
,
Lanske
B.
,
Kronenberg
H.
,
Karaplis
A.
,
Broadus
A. E.
(
1998
)
Rescue of the parathyroid hormone-related protein knockout mouse demonstrates that parathyroid hormone-related protein is essential for mammary gland development.
Development
125
,
1285
1294
Zhou
P.
,
Byrne
C.
,
Jacobs
J.
,
Fuchs
E.
(
1995
)
Lymphoid enhancer factor 1 directs hair follicle patterning and epithelial cell fate.
Genes Dev
9
,
700
713
Zhu
A. J.
,
Watt
F. M.
(
1999
)
beta-catenin signalling modulates proliferative potential of human epidermal keratinocytes independently of intercellular adhesion.
Development
126
,
2285
2298
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