The severity of mammary gland developmental defects is linked to the overall functional status of Cx43 as revealed by genetically modified mice.
Genetically modified mice mimicking ODDD (oculodentodigital dysplasia), a disease characterized by reduced Cx43 (connexin 43)-mediated gap junctional intercellular communication, represent an in vivo model to assess the role of Cx43 in mammary gland development and function. We previously reported that severely compromised Cx43 function delayed mammary gland development and impaired milk ejection in mice that harboured a G60S Cx43 mutant, yet there are no reports of lactation defects in ODDD patients. To address this further, we obtained a second mouse model of ODDD expressing an I130T Cx43 mutant to assess whether a mutant with partial gap junction channel activity would be sufficient to retain mammary gland development and function. The results of the present study show that virgin Cx43I130T/+ mice exhibited a temporary delay in ductal elongation at 4 weeks. In addition, Cx43I130T/+ mice develop smaller mammary glands at parturition due to reduced cell proliferation despite similar overall gland architecture. Distinct from Cx43G60S/+ mice, Cx43I130T/+ mice adequately produce and deliver milk to pups, suggesting that milk ejection is unaffected. Thus the present study suggests that a loss-of-function mutant of Cx43 with partial gap junction channel coupling conductance results in a less severe mammary gland phenotype, which may partially explain the lack of reported lactation defects associated with ODDD patients.
Department of Physiology and Pharmacology, Western University, London, ON, Canada N6A 5C1.
Michael K G
MK
Stewart
Xiang-Qun
XQ
Gong
Kevin J
KJ
Barr
Donglin
D
Bai
Glenn I
GI
Fishman
Dale W
DW
Laird
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018031:Connexin 43 / Q000235:genetics* / Q000378:metabolism; D019465:Craniofacial Abnormalities / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D005124:Eye Abnormalities / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D005532:Foot Deformities, Congenital / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017629:Gap Junctions / Q000378:metabolism / Q000473:pathology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007774:Lactation / Q000187:drug effects / Q000235:genetics; D008297:Male; D008321:Mammary Glands, Animal / Q000002:abnormalities* / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D010121:Oxytocin / Q000494:pharmacology; D017354:Point Mutation; D011247:Pregnancy; D012720:Severity of Illness Index; D013576:Syndactyly / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014071:Tooth Abnormalities / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D018031:Connexin 43; D049452:Green Fluorescent Proteins; D010121:Oxytocin