Phenotypic and Molecular Alterations in the Mammary Tissue of R-Spondin1 Knock-Out Mice during Pregnancy

Abstract

R-spondin1 (Rspo1) is a member of a secreted protein family which has pleiotropic functions in development and stem cell growth. Rspo1 knock-out mice are sex-reversed, but some remain sub-fertile, so they fail to nurse their pups. A lack of Rspo1 expression in the mammary gland results in an absence of duct side-branching development and defective alveolar formation. The aim of this study was to characterize the phenotypic and molecular alterations of mammary gland due to Rspo1 knock-out. Using the transcriptional profiling of mammary tissues, we identified misregulated genes in the mammary gland of Rspo1 knock-out mice during pregnancy. A stronger expression of mesenchymal markers was observed, without modifications to the structure of mammary epithelial tissue. Mammary epithelial cell immunohistochemical analysis revealed a persistence of virgin markers, which signify a delay in cell differentiation. Moreover, serial transplantation experiments showed that Rspo1 is associated with a regenerative potential of mammary epithelial cell control. Our finding also highlights the negatively regulated expression of Rspo1’s partners, Lgr4 and RNF43, in the mammary gland during pregnancy. Moreover, we offer evidence that Tgf-β signalling is modified in the absence of Rspo1. Taken together, our results show an abrupt halt or delay to mammary development during pregnancy due to the loss of a further differentiated function.

Amorphous polyphosphate, a smart bioinspired nano-/bio-material for bone and cartilage regeneration: towards a new paradigm in tissue engineering

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R‐spondin‐mediated WNT signaling potentiation in mammary and breast cancer development

“…14,32 Regarding the mammary gland, it was reported that Rspo1 (−/−) mice were unable to feed their pups, 71 and that transplants of their glands into cleared fat pads of wild-type mice showed impaired sidebranching in virgin females and reduced alveolar formation with a persistence of virgin markers during pregnancy. 72,73 Importantly, it has been shown that RSPO1 expression is induced in ER − PR − mammary cells of wildtype mice during pregnancy or upon treatment with estrogen, progesterone, or both hormones. 74 These results indicated that sex hormones would cause the secretion of a mediator that, in turn, would trigger RSPO1 synthesis in ER − PR − mammary cells.…”