Cnnm4 deficiency suppresses Ca²⁺ signaling and promotes cell proliferation in the colon epithelia

CNNM4 is a Mg²⁺ transporter highly expressed in the colon epithelia. Its importance in regulating intracellular Mg²⁺ levels and cancer development has been documented, but how CNNM4 function affects the dynamic homeostasis of the epithelial tissue remains unclear. Here, we show that Cnnm4 deficiency promotes cell proliferation and partly suppresses cell differentiation in the colon epithelia, making them vulnerable to cancer development. Such phenotypic characteristics are highly similar to those of mice lacking Trpv1, which encodes the cation channel involved in capsaicin-stimulated Ca²⁺ influx. Indeed, Ca²⁺-imaging analyses using the organoid culture reveal that Ca²⁺ influx stimulated by capsaicin is greatly impaired by Cnnm4 deficiency. Moreover, EGF receptor signaling is constitutively activated in the colon epithelia of Cnnm4-deficient mice, as is the case with Trpv1-deficient mice. The administration of gefitinib, a clinically available inhibitor of EGF receptor, cancels the augmented proliferation of cells observed in Cnnm4-deficient mice. Collectively, these results establish the functional interplay between Mg²⁺ and Ca²⁺ in the colon epithelia, which is crucial for maintaining the dynamic homeostasis of the epithelial tissue.