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R-spondin1 (Rspo1) has been featured as a Wnt agonist, serving as a potent niche factor for stem cells in many tissues. Here we unveil a novel role of Rspo1 in promoting  estrogen receptor alpha (Esr1)  expression, hence regulating the output of steroid hormone signaling in the mouse mammary gland. This action of Rspo1 relies on the receptor Lgr4 and intracellular cAMP-PKA signaling, yet is independent of Wnt/β-catenin signaling. These mechanisms were reinforced by genetic evidence. Luminal cells-specific knockout of  Rspo1  results in decreased  Esr1  expression and reduced mammary side branches. In contrast, luminal cells-specific knockout of  Wnt4 , while attenuating basal cell Wnt/β-catenin signaling activities, enhances  Esr1  expression. Our data reveal a novel Wnt-independent role of Rspo1, in which Rspo1 acts as a bona fide GPCR activator eliciting intracellular cAMP signaling. The identification of Rspo1-ERα signaling axis may have a broad implication in estrogen-associated diseases.

A novel function of R-spondin1 in regulating estrogen receptor expression independent of Wnt/β-catenin signaling