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© The Rockefeller University Press, 0021-9525/1999//77 $5.00
The Journal of Cell Biology, Volume 147, Number 1, , 1999 77-88

Original Article

Erbb4 Signaling in the Mammary Gland Is Required for Lobuloalveolar Development and Stat5 Activation during Lactation



Frank E. Jonesa, Thomas Weltea, Xin-Yuan Fua, and David F. Sterna

a Department of Pathology, BML 342, Yale University School of Medicine, New Haven, Connecticut 06520-8023
Department of Pathology, BML 342, Yale University School of Medicine, P.O. Box 208023, New Haven, CT 06520-8023.(203) 785-7467(203) 785-4832

stern{at}biomed.med.yale.edu

Signaling by members of the epidermal growth factor receptor family plays an important role in breast development and breast cancer. Earlier work suggested that one of these receptors, ErbB4, is coupled to unique responses in this tissue. To determine the function of ErbB4 signaling in the normal mouse mammary gland, we inactivated ErbB4 signaling by expressing a COOH terminally deleted dominant-negative allele of ErbB4 (ErbB4{Delta}IC) as a transgene in the mammary gland. Despite the expression of ErbB4{Delta}IC from puberty through later stages of mammary development, an ErbB4{Delta}IC-specific phenotype was not observed until mid-lactation. At 12-d postpartum, lobuloalveoli expressing ErbB4{Delta}IC protein were condensed and lacked normal lumenal lactation products. In these lobuloalveoli, β-casein mRNA, detected by in situ hybridization, was normal. However, whey acidic protein mRNA was reduced, and {alpha}-lactalbumin mRNA was undetectable. Stat5 expression was detected by immunohistochemistry in ErbB4{Delta}IC-expressing tissue. However, Stat5 was not phosphorylated at Y694 and was, therefore, probably inactive. When expressed transiently in 293T cells, ErbB4 induced phosphorylation of Stat5. This phosphorylation required an intact Stat5 SH2 domain. In summary, our results demonstrate that ErbB4 signaling is necessary for mammary terminal differentiation and Stat5 activation at mid-lactation.

Key Words: ErbB4 • Stat5 • dominant-negative mutant • transgenic mice • mammary gland development

© 1999 The Rockefeller University Press

1.used in this paper: EGFR, epidermal growth factor receptor; LPrlR, long prolactin receptor isoform; MMTV, mouse mammary tumor virus; NRG1, neuregulin-1; PrlR, prolactin receptor; SPrlR, short prolactin receptor isoform; Stat, signal transducers and activators of transcription; TGF{alpha}, transforming growth factor {alpha}; WAP, whey acidic protein

Frank E. Jones' current address is University of Scranton, Institute of Molecular Biology and Medicine, Scranton, PA 18510.


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