Abstract
Connexin26 (Cx26) is the major Cx protein expressed in the human mammary gland and is up-regulated during pregnancy while remaining elevated throughout lactation. It is currently unknown if patients with loss-of-function Cx26 mutations that result in hearing loss and skin diseases have a greater susceptibility to impaired breast development. To investigate if Cx26 plays a critical role in mammary gland development and differentiation, a novel Cx26 conditional knockout mouse model was generated by crossing Cx26fl/fl mice with mice expressing Cre under the β-Lactoglobulin promoter. Conditional knockdown of Cx26 from the mammary gland resulted in a dramatic reduction in detectable gap junction plaques confirmed by a significant ∼65-70% reduction in Cx26 mRNA and protein throughout parturition and lactation. Interestingly, this reduction was accompanied by a decrease in mammary gland Cx30 gap junction plaques at parturition, while no change was observed for Cx32 or Cx43. Whole mount, histological and immunofluorescent assessment of breast tissue revealed comparatively normal lobuloalveolar development following pregnancy in the conditionally knockdown mice compared to control mice. In addition, glands from genetically-modified mice were capable of producing milk proteins that were evident in the lumen of alveoli and ducts at similar levels as controls, suggesting normal gland function. Together, our results suggest that low levels of Cx26 expression throughout pregnancy and lactation, and not the physiological surge in Cx26, is sufficient for normal gland development and function.
Highlights
Breast morphogenesis is unique to other organ systems in that the majority of its development occurs after birth
To assess the status of other connexins co-expressed within the mammary gland in response to a reduction in Cx26, Western blot and immunofluorescent analysis of Cx43, Cx32 and Cx30 were evaluated at parturition and lactation
Cx26 is the only consistently reported connexin to date to be expressed within the luminal epithelium suggesting that Cx26 is the dominant connexin regulating human mammary gland function [3]
Summary
Breast morphogenesis is unique to other organ systems in that the majority of its development occurs after birth. The mammary gland of mice is comparable to that of humans and has frequently been used as a model to study mammary gland development [2]. Much is known about the hormonal control of mammary gland throughout development, less is known about local communication such as the gap junction proteins connexins (Cxs) [3], [4]. Gap junctions have been shown to play a role in coordinating cellular tissue responses downstream of hormonal/paracrine stimuli suggesting that dysregulation of Cxs may alter hormonally controlled organ development and function [5]
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