Loss of connexin 26 in mammary epithelium during early but not during late pregnancy results in unscheduled apoptosis and impaired development.
Gap junctions are intercellular channels that are formed by the protein family of connexins (Cxs). In mammary tissue, Cx26 and Cx32 are present in the secretory epithelium and Cx43 is localized in the myoepithelium. The expression of Cx26 and Cx32 is induced during pregnancy and lactation, respectively, thus suggesting unique roles for them in the functional development of the gland. The requirement for these connexins was explored using several strains of genetically altered mice: mice with an inactivated Cx32 gene, mice in which the Cx43 gene had been replaced with the Cx32 gene (Cx43KI32 mice) and mice in which the Cx26 gene was specifically ablated in mammary epithelium at different stages of development using Cre-loxP-based recombination. Normal mammary development was obtained in Cx32-null mice and in Cx43KI32 mammary tissue. In contrast, loss of Cx26 in mammary epithelium before puberty resulted in abrogated lobulo-alveolar development and increased cell death during pregnancy, which was accompanied by impaired lactation. Loss of Cx26 in mammary epithelium during the later part of pregnancy did not adversely interfere with functional mammary development. These results demonstrate that the presence of Cx26 is critical during early stages but not during the end of pregnancy when the tissue has completed functional differentiation. Cx26 is considered a tumor suppressor gene and Cx26-null mammary tissue was evaluated after five pregnancies. No hyperproliferation or hyperplasia was observed, suggesting that Cx26 does not function as a tumor suppressor.
Bry
Céline
C
Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Maass
Karen
K
Miyoshi
Keiko
K
Willecke
Klaus
K
Ott
Thomas
T
Robinson
Gertraud W
GW
Hennighausen
Lothar
L
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D015139:Blotting, Southern; D000072259:Connexin 26; D017630:Connexins / Q000172:deficiency* / Q000235:genetics; D017931:DNA Primers; D004848:Epithelium / Q000254:growth & development; D005260:Female; D006652:Histological Techniques; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007774:Lactation / Q000235:genetics / Q000502:physiology*; D008321:Mammary Glands, Animal / Q000166:cytology / Q000254:growth & development*; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000502:physiology*; D019076:Transgenes / Q000235:genetics
D017630:Connexins; D017931:DNA Primers; C000607043:Gjb2 protein, mouse; D000072259:Connexin 26