Differential mammary morphogenesis along the anteroposterior axis in Hoxc6 gene targeted mice.
Mammary epithelial cell proliferation, branching, and differentiation span from the appearance of the mammary bud in midgestation through to the cycling mammary gland in adulthood. Here, we show that females homozygous for a targeted disruption of the Hoxc6 homeobox gene produce thoracic mammary glands that are slightly under-developed at birth and completely cleared of epithelium by adulthood, and inguinal mammary ducts that are dilated and fail to regress in response to ovariectomy. Mammary buds are detected in E12.5 Hoxc6 homozygous embryos. However, in newborn Hoxc6 homozygous females, branching ductal structures and fat pad development are reduced. Whole-mount and histologic analyses of mammary glands from adult Hoxc6 homozygous females show the absence of mammary epithelium in thoracic glands and dilated ducts in inguinal glands at 100% penetrance. Histologic analysis of inguinal mammary glands from ovariectomized Hoxc6 homozygous females demonstrates no signs of the expected regression of epithelium, suggesting that these glands are not responsive to the loss of ovarian hormone signals. We further observe repression of Hoxc6 expression specifically within mammary stroma by estrogen and progesterone. Hoxc6 homozygous mice also exhibit a homeotic transformation of the second thoracic vertebra into the first (T2 to T1 conversion with 60% penetrance), corresponding to both the gene's anterior boundary of expression and the most extreme appearance of mammary defects. The position-specific phenotypes observed and the potential role for Hoxc6 in mediating hormone-regulated ductal expansion and regression in the adult female are discussed.
Garcia-Gasca
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Center for Molecular and Structural Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29403, USA.
Spyropoulos
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D016475:3T3 Cells; D000015:Abnormalities, Multiple / Q000196:embryology / Q000235:genetics; D000818:Animals; D019521:Body Patterning / Q000235:genetics*; D001943:Breast Neoplasms; D002454:Cell Differentiation; D004847:Epithelial Cells / Q000166:cytology; D004967:Estrogens / Q000502:physiology; D005260:Female; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008321:Mammary Glands, Animal / Q000196:embryology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009024:Morphogenesis / Q000235:genetics*; D011374:Progesterone / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D004967:Estrogens; C094289:HOXC6 protein, human; D018398:Homeodomain Proteins; C080041:Hoxc6 protein, mouse; D011994:Recombinant Proteins; D011374:Progesterone