Abstract
PTPRB is a transmembrane protein tyrosine phosphatase known to regulate blood vessel remodelling and angiogenesis. Here, we demonstrate that PTPRB negatively regulates branching morphogenesis in the mouse mammary epithelium. We show that Ptprb is highly expressed in adult mammary stem cells and also, although at lower levels, in oestrogen receptor-positive luminal cells. During mammary development, Ptprb expression is downregulated during puberty, a period of extensive ductal outgrowth and branching. In vivo shRNA knockdown of Ptprb in the cleared mammary fat pad transplant assay resulted in smaller epithelial outgrowths with an increased branching density and also increased branching in an in vitro organoid assay. Organoid branching was dependent on stimulation by FGF2, and Ptprb knockdown in mammary epithelial cells resulted in a higher level of fibroblast growth factor receptor (FGFR) activation and ERK1/2 phosphorylation, both at baseline and following FGF2 stimulation. Therefore, PTPRB regulates branching morphogenesis in the mammary epithelium by modulating the response of the FGFR signalling pathway to FGF stimulation. Considering the importance of branching morphogenesis in multiple taxa, our findings have general importance outside mammary developmental biology.
Highlights
The mammary gland is a highly dynamic organ; limited embryonic development is followed by extensive postnatal pubertal development with further differentiation and tissue remodelling occurring during pregnancy and lactation (Macias and Hinck, 2012)
We recently identified a set of 323 genes, including Ptprb, expression of which was associated with the transplantable basal mammary stem cell (MaSC) population in the adult mouse mammary epithelium (Soady et al, 2015)
We evaluated Ptprb expression by quantitative real-time reverse transcriptase PCR during postnatal mammary gland development in highly purified primary mammary epithelium subpopulations isolated by flow cytometry at three developmental time points
Summary
The mammary gland is a highly dynamic organ; limited embryonic development is followed by extensive postnatal pubertal development with further differentiation and tissue remodelling occurring during pregnancy and lactation (Macias and Hinck, 2012). Stem cells dispersed throughout the mature mammary epithelium are thought to be important for maintenance of the adult nonpregnant gland, the nature of these remains controversial (Rios et al, 2014; Van Keymeulen et al, 2011; Wang et al, 2015) It is clear, that the basal layer contains a small population of cells with potent outgrowth potential that, upon mammary fat pad transplantation, are able to regenerate complete basal and luminal layers, consistent with a stem cell identity (Shackleton et al, 2006; Sleeman et al, 2006; Stingl et al, 2006). The molecular regulation of epithelial homeostasis in these stemprogenitor-differentiated populations, and how this homeostasis contributes to tissue morphogenesis, remains an area of intense interest
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