help button home button Endocrine Society Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hom, Y. K.
Right arrow Articles by Cunha, G. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hom, Y. K.
Right arrow Articles by Cunha, G. R.
Endocrinology Vol. 139, No. 3 913-921
Copyright © 1998 by The Endocrine Society

ARTICLES

Uterine and Vaginal Organ Growth Requires Epidermal Growth Factor Receptor Signaling from Stroma1

Yun Kit Hom, Peter Young, Jane F. Wiesen, Päivi J. Miettinen, Rik Derynck, Zena Werb and Gerald R. Cunha

Department of Anatomy (Y.K.H., P.Y., J.F.W., Z.W., G.R.C.) and Department of Growth and Development (P.J.M., R.D.), University of California, San Francisco, California 94143

Address all correspondence and requests for reprints to: Dr. Gerald R. Cunha, Department of Anatomy, Mail Stop 0452, University of California, San Francisco, California 94143. E-mail: grcunha{at}itsa.ucsf.edu

Estrogens are crucial for growth and function of the female genital tract. Recently, we showed that induction of uterine epithelial proliferation by estradiol is a paracrine event requiring an estrogen receptor-positive stroma. Growth factors [such as EGF (epidermal growth factor) ligands] are likely paracrine mediators, which may directly or indirectly regulate epithelial proliferation in estrogen target organs via cell-cell interactions. In this report, we used mice with a null mutation in their EGF receptor (EGFR) to examine the role of EGFR signaling in growth of the uterus and vagina and in estrogen-induced uterine and vaginal epithelial proliferation. When WT and EGFR-knockout (EGFR-KO) uteri and vaginae were grown as renal capsule grafts in nude mice, growth of uterine and vaginal grafts of EGFR-KO mice was reduced, compared with their WT counterparts. Grafts of both EGFR-KO uteri and vaginae were about one third smaller (wet weight) than their corresponding WT organs, even though differentiation of both epithelium and mesenchyme were normal in both cases. Both wild-type and EGFR-KO vaginal grafts contained within their lumina alternating layers of cornified and mucified epithelial cell layers, indicating cyclic alteration of epithelial differentiation. In response to estradiol treatment, stromal cell labeling index (LI), as assessed by incorporation of 3H-thymidine, was severely depressed in EGFR-KO uterine and vaginal grafts vs. stromal cell LI in WT uterine and vaginal grafts. Unexpectedly, epithelium of both EGFR-KO and wild-type grafts responded comparably to estradiol with a marked elevation (~7-fold overall) of epithelial LI in response to estradiol in uterine and vaginal epithelia. These data supported the hypothesis that overall uterine and vaginal organ growth, in response to estrogen, required EGFR signaling for DNA synthesis in the fibromuscular stroma, whereas EGFR signaling was not essential for estrogen-induced epithelial growth in the uterus and vagina.




This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
T. Hitosugi, K. Sasaki, M. Sato, Y. Suzuki, and Y. Umezawa
Epidermal Growth Factor Directs Sex-specific Steroid Signaling through Src Activation
J. Biol. Chem., April 6, 2007; 282(14): 10697 - 10706.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
G. I. Gorodeski
Estrogen Modulation of MgATPase Activity of Nonmuscle Myosin-II-B Filaments
Endocrinology, January 1, 2007; 148(1): 279 - 292.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
O. Wada-Hiraike, H. Hiraike, H. Okinaga, O. Imamov, R. P. A. Barros, A. Morani, Y. Omoto, M. Warner, and J.-A. Gustafsson
Role of estrogen receptor beta in uterine stroma and epithelium: Insights from estrogen receptor beta-/- mice
PNAS, November 28, 2006; 103(48): 18350 - 18355.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
X. Li, L. Zhou, and G. I. Gorodeski
Estrogen Regulates Epithelial Cell Deformability by Modulation of Cortical Actomyosin through Phosphorylation of Nonmuscle Myosin Heavy-Chain II-B Filaments
Endocrinology, November 1, 2006; 147(11): 5236 - 5248.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
A. Suzuki, H. Watanabe, T. Mizutani, T. Sato, Y. Ohta, and T. Iguchi
Global Gene Expression in Mouse Vaginae Exposed to Diethylstilbestrol at Different Ages.
Experimental Biology and Medicine, May 1, 2006; 231(5): 632 - 640.
[Abstract] [Full Text] [PDF]

Home page
 GutHome page
K Ishiguro, T Yoshida, H Yagishita, Y Numata, and T Okayasu
Epithelial and stromal genetic instability contributes to genesis of colorectal adenomas
Gut, May 1, 2006; 55(5): 695 - 702.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
K. Inada, S. Hayashi, T. Iguchi, and T. Sato
Establishment of a primary culture model of mouse uterine and vaginal stroma for studying in vitro estrogen effects.
Experimental Biology and Medicine, March 1, 2006; 231(3): 303 - 310.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
H. Okada, G. Nie, and L. A. Salamonsen
Requirement for Proprotein Convertase 5/6 during Decidualization of Human Endometrial Stromal Cells in Vitro
J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 1028 - 1034.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
L. Wang, Y.-H. Feng, and G. I. Gorodeski
Epidermal Growth Factor Facilitates Epinephrine Inhibition of P2X7-Receptor-Mediated Pore Formation and Apoptosis: A Novel Signaling Network
Endocrinology, January 1, 2005; 146(1): 164 - 174.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
R. X. Song, C. J. Barnes, Z. Zhang, Y. Bao, R. Kumar, and R. J. Santen
The role of Shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor {alpha} to the plasma membrane
PNAS, February 17, 2004; 101(7): 2076 - 2081.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
K. H. H. Wong, H. D. Wintch, and M. R. Capecchi
Hoxa11 Regulates Stromal Cell Death and Proliferation during Neonatal Uterine Development
Mol. Endocrinol., January 1, 2004; 18(1): 184 - 193.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
N. Matsumoto, T. Yoshida, and I. Okayasu
High Epithelial and Stromal Genetic Instability of Chromosome 17 in Ulcerative Colitis-associated Carcinogenesis
Cancer Res., October 1, 2003; 63(19): 6158 - 6161.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
K. S. Grant and C. R. Wira
Effect of Mouse Uterine Stromal Cells on Epithelial Cell Transepithelial Resistance (TER) and TNF{alpha} and TGF{beta} Release in Culture
Biol Reprod, September 1, 2003; 69(3): 1091 - 1098.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
E. R. Levin
Bidirectional Signaling between the Estrogen Receptor and the Epidermal Growth Factor Receptor
Mol. Endocrinol., March 1, 2003; 17(3): 309 - 317.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
G.-Y. Nie, Y. Li, H. Minoura, J. K. Findlay, and L. A. Salamonsen
Specific and Transient Up-Regulation of Proprotein Convertase 6 at the Site of Embryo Implantation and Identification of a Unique Transcript in Mouse Uterus During Early Pregnancy
Biol Reprod, February 1, 2003; 68(2): 439 - 447.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
M. Jakacka, M. Ito, F. Martinson, T. Ishikawa, E. J. Lee, and J. L. Jameson
An Estrogen Receptor (ER){alpha} Deoxyribonucleic Acid-Binding Domain Knock-In Mutation Provides Evidence for Nonclassical ER Pathway Signaling in Vivo
Mol. Endocrinol., October 1, 2002; 16(10): 2188 - 2201.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
R. B. Roberts, L. Min, M. K. Washington, S. J. Olsen, S. H. Settle, R. J. Coffey, and D. W. Threadgill
Importance of epidermal growth factor receptor signaling in establishment of adenomas and maintenance of carcinomas during intestinal tumorigenesis
PNAS, January 24, 2002; (2002) 32678499.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
K. Kurose, S. Hoshaw-Woodard, A. Adeyinka, S. Lemeshow, P. H. Watson, and C. Eng
Genetic model of multi-step breast carcinogenesis involving the epithelium and stroma: clues to tumour-microenvironment interactions
Hum. Mol. Genet., September 1, 2001; 10(18): 1907 - 1913.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
M. P. V. Shekhar, J. Werdell, S. J. Santner, R. J. Pauley, and L. Tait
Breast Stroma Plays a Dominant Regulatory Role in Breast Epithelial Growth and Differentiation: Implications for Tumor Development and Progression
Cancer Res., February 1, 2001; 61(4): 1320 - 1326.
[Abstract] [Full Text]

Home page
 Cancer Res.Home page
F. Moinfar, Y. G. Man, L. Arnould, G. L. Bratthauer, M. Ratschek, and F. A. Tavassoli
Concurrent and Independent Genetic Alterations in the Stromal and Epithelial Cells of Mammary Carcinoma: Implications for Tumorigenesis
Cancer Res., May 1, 2000; 60(9): 2562 - 2566.
[Abstract] [Full Text]

Home page
 Endocr. Rev.Home page
J. F. Couse and K. S. Korach
Estrogen Receptor Null Mice: What Have We Learned and Where Will They Lead Us?
Endocr. Rev., June 1, 1999; 20(3): 358 - 417.
[Abstract] [Full Text]

Home page
 EndocrinologyHome page
T. Kurita, P. Young, J. R. Brody, J. P. Lydon, B. W. O'Malley, and G. R. Cunha
Stromal Progesterone Receptors Mediate the Inhibitory Effects of Progesterone on Estrogen-Induced Uterine Epithelial Cell Deoxyribonucleic Acid Synthesis
Endocrinology, November 1, 1998; 139(11): 4708 - 4713.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
R. B. Roberts, L. Min, M. K. Washington, S. J. Olsen, S. H. Settle, R. J. Coffey, and D. W. Threadgill
Importance of epidermal growth factor receptor signaling in establishment of adenomas and maintenance of carcinomas during intestinal tumorigenesis
PNAS, February 5, 2002; 99(3): 1521 - 1526.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 1998 by The Endocrine Society