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Development, Vol 126, Issue 12 2739-2750, Copyright © 1999 by Company of Biologists
JOURNAL ARTICLES |
NC Luetteke, TH Qiu, SE Fenton, KL Troyer, RF Riedel, A Chang and DC Lee
Department of Biochemistry and Biophysics, UNC Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7295, USA.
Targeted mice lacking functional EGF or amphiregulin (AR) were derived and bred to the TGFalpha-knockout to generate mice lacking various combinations of the three ligands. In contrast to EGF receptor (EGFR) knockout mice, triple null mice lacking half of the EGFR ligand family were healthy and fertile, indicative of overlapping or compensatory functions among EGF family members. Nevertheless, pups born to triple null dams frequently died or were runted, suggesting a mammary gland defect. Comparison of individual and combinatorial knockouts established that specific loss of AR severely stunted ductal outgrowth during puberty, consistent with dramatic expression of AR transcripts in normal developing ducts. Surprisingly, loss of all three ligands did not significantly affect cellular proliferation, apoptosis, or ERK activation within terminal end buds. Following pregnancy, most AR single null females, but few triple null females could nurse their young, revealing collaborative roles for EGF and TGFalpha in mammopoiesis and lactogenesis. In triple null glands, alveoli were poorly organized and differentiated, and milk protein gene expression was decreased. Additionally, Stat5a activation was frequently reduced in AR single and combinatorial nulls in association with impaired lactation. Collectively, our results provide genetic confirmation of a requirement for EGFR signaling throughout the development of the mouse mammary gland, and reveal stage-dependent activities for different EGFR ligands. Finally, the additional loss of growth factors from pups nursed by triple null dams further worsened their survival and growth, establishing functions for both maternal- and neonatal-derived growth factors.
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 S. GEYMAYER and W. DOPPLER Activation of NF-{kappa}B p50/p65 is regulated in the developing mammary gland and inhibits STAT5-mediated {beta}-casein gene expression FASEB J, June 1, 2000; 14(9): 1159 - 1170. [Abstract] [Full Text]
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 G. W. Robinson, L. Hennighausen, and P. F. Johnson Side-branching in the mammary gland: the progesterone-Wnt connection Genes & Dev., April 15, 2000; 14(8): 889 - 894. [Full Text]
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 A. S. Giraud Lessons From Genetically Engineered Animal Models: X. Trefoil peptide and EGF receptor/ligand transgenic mice Am J Physiol Gastrointest Liver Physiol, April 1, 2000; 278(4): G501 - G506. [Abstract] [Full Text] [PDF]
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T. N. Seagroves, J. P. Lydon, R. C. Hovey, B. K. Vonderhaar, and J. M. Rosen C/EBP{beta} (CCAAT/Enhancer Binding Protein) Controls Cell Fate Determination during Mammary Gland Development Mol. Endocrinol., March 1, 2000; 14(3): 359 - 368. [Abstract] [Full Text]
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 G. Carpenter EGF Receptor Transactivation Mediated by the Proteolytic Production of EGF-like Agonists Sci. Signal., January 18, 2000; 2000(15): pe1 - pe1. [Abstract] [Full Text] [PDF]
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F. E. Jones, T. Welte, X.-Y. Fu, and D. F. Stern ErbB4 Signaling in the Mammary Gland Is Required for Lobuloalveolar Development and Stat5 Activation during Lactation J. Cell Biol., October 4, 1999; 147(1): 77 - 88. [Abstract] [Full Text] [PDF]
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R. W.-C. Wong, R. W.-P. Kwan, P. H.-S. Mak, K. K.-L. Mak, M.-H. Sham, and S.-Y. Chan Overexpression of Epidermal Growth Factor Induced Hypospermatogenesis in Transgenic Mice J. Biol. Chem., June 9, 2000; 275(24): 18297 - 18301. [Abstract] [Full Text] [PDF]
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S.-Y. Chan and R. W.-C. Wong Expression of Epidermal Growth Factor in Transgenic Mice Causes Growth Retardation J. Biol. Chem., December 1, 2000; 275(49): 38693 - 38698. [Abstract] [Full Text] [PDF]
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L. Strachan, J. G. Murison, R. L. Prestidge, M. A. Sleeman, J. D. Watson, and K. D. Kumble Cloning and Biological Activity of Epigen, a Novel Member of the Epidermal Growth Factor Superfamily J. Biol. Chem., May 18, 2001; 276(21): 18265 - 18271. [Abstract] [Full Text] [PDF]
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