Targeted inactivation of the EGF and amphiregulin genes reveals distinct roles for EGF receptor ligands in mouse mammary gland development

Development (Cambridge) - Tập 126 Số 12 - Trang 2739-2750 - 1999
Noreen Luetteke1,2, Ting Qiu2, Suzanne E. Fssssenton2, Kelly L. Troyer3, Richard F. Riedel2, Aileen Y. Chang2, David C. Lee1,2,3
11 Department of Biochemistry and Biophysics
22 UNC Lineberger Comprehensive Cancer Center
33 Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7295, USA

Tóm tắt

SUMMARY Targeted mice lacking functional EGF or amphiregulin (AR) were derived and bred to the TGFα-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 TGFα 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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Tài liệu tham khảo

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Development (Cambridge)

Tập 126 Số 12

2739-2750

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