Impaired differentiation and lactational failure of Erbb4-deficient mammary glands identify ERBB4 as an obligate mediator of STAT5.
The ERBB family of type 1 receptor tyrosine kinases and their ligands have crucial functions during mammopoiesis, but the signaling networks that ultimately regulate ERBB activity in the breast have remained elusive. Here, we show that mice with Cre-lox mediated deletions of both Erbb4 alleles within the developing mammary gland (Erbb4(Flox/Flox)Wap-Cre) fail to accumulate lobuloalveoli or successfully engage lactation at parturition owing, in part, to impaired epithelial proliferation. Analysis of the mammary differentiation factor STAT5 by immunohistochemistry and western blot revealed a complete ablation of STAT5 activation in Erbb4(Flox/Flox)Wap-Cre mammary epithelium at parturition. Consistent with disrupted STAT5 function, Erbb4(Flox/Flox)Wap-Cre mammary glands at parturition failed to express the mammary epithelial differentiation marker NPT2B. Defects in epithelial functional differentiation at parturition were accompanied by a profound reduction in expression of the STAT5-regulated milk genes casein beta and whey acidic protein. We propose that ERBB4 functions as an essential mediator of STAT5 signaling, and that loss of STAT5 activity contributes to the impaired functional differentiation of mammary glands observed in mice containing conditional Erbb4 deletions.
Long
Weiwen
W
Department of Structural and Cellular Biology, Tulane Cancer Center, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, Louisiana 70112-2699, USA.
Wagner
Kay-Uwe
KU
Lloyd
K C Kent
KC
Binart
Nadine
N
Shillingford
Jonathan M
JM
Hennighausen
Lothar
L
Jones
Frank E
FE
D000818:Animals; D002364:Caseins / Q000235:genetics; D002454:Cell Differentiation / Q000502:physiology*; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D004848:Epithelium / Q000033:anatomy & histology / Q000502:physiology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D007774:Lactation / Q000502:physiology*; D008321:Mammary Glands, Animal / Q000166:cytology / Q000254:growth & development / Q000502:physiology*; D051379:Mice; D008894:Milk Proteins / Q000235:genetics; D011247:Pregnancy; D066247:Receptor, ErbB-4; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
D002364:Caseins; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; D015534:Trans-Activators; C024471:whey acidic proteins; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4