Na⁺/H⁺ exchanger 1 (NHE1) function is necessary for maintaining mammary tissue architecture

Abstract

Background: The mammary gland is an ideal model to study the link between form and function in normal tissue. Perhaps as interesting as the cues necessary to generate this structure are the signals required to maintain its branched architecture over the lifetime of the organism, since likely these pathways are de-regulated in malignancies. Previously, we have shown that the Na 1 /H 1 exchanger 1 (NHE1), a critical regulator of intracellular pH, was necessary for mammary branching morphogenesis. Here we provide strong evidence that NHE1 function is also necessary for maintaining mammary branched architecture. Results: Inhibition of NHE1 with 5-N-Methy-N-isobutyl amiloride (MIA) on branched structures resulted in a rapid (within 24 hr) and reversible loss of branched architecture that was not accompanied by any overt changes in cell proliferation or cell death. NHE1 inhibition led to a significant acidification of intracellular pH in the branched end buds that preceded a number of events, including altered tissue polarity of myoepithelial cells, loss of NHE1 basal polarity, F-actin rearrangements, and decreased Ecadherin expression. Conclusions: Our results implicate NHE1 function and intracellular pH homeostasis as key factors that maintain mammary tissue architecture, thus, indirectly allowing for mammary function as a milk-providing (form) and -producing (function) gland. Developmental Dynamics 243:229-242, 2014. V C 2013 Wiley Periodicals, Inc.Key words: mammary tissue architecture; mammary epithelial ducts; sodium hydrogen exchanger; NHE1; intracellular pH; tissue polarity; cellular polarity Key Findings:NHE1 inhibition causes a rapid loss of mammary branched architecture. NHE1 function is necessary for mammary tissue organization and cellular polarity. NHE1 inhibition decreases E-cadherin expression.

Cutaneous pH landscape as a facilitator of melanoma initiation and progression

“…So far, it is not known whether the process of decoupling itself is also regulated by an altered pH homoeostasis, induced, for example, by the BRAF V600E ‐mediated stimulation of NHE1 . Studies made with organoid cultures of mammary glands, however, revealed that the expression of E‐cadherin is downregulated by NHE1 inhibition …”

Characterization of intracellular buffering power in human induced pluripotent stem cells and the loss of pluripotency is delayed by acidic stimulation and increase of NHE1 activity

“…The growth factor‐induced intracellular alkalization was blocked by the NHE1 specific inhibitor, MIA, and disrupted the mammary branching morphogenesis. In this model, treatment with MIA caused the whole primary mammary tissue acidification (Jenkins, Debnath, Varriano, Gundry, & Fata, 2014; Jenkins et al, 2012). Moreover, activation of NHE1 increased the pH i on the side of lamellipodia more than on the other side, and this gradient collapsed upon the inhibition of NHE1 (Denker & Barber, 2002).…”