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Rspo1 role in mammary gland 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 are unable to nurse their pups. A lack of Rspo1 expression in mammary epithelial cells results in an absence of duct side-branching development and defective alveolar formation. In this study we propose to characterize the molecular functions involved to mammary gland phenotype due to Rspo1 knock out. By transcriptional profiling, we have identified gene misregulated in mammary gland of Rspo1 knock-out mice during pregnancy. A stronger expression of genes characterising mesenchymal tissue was observed in the absence of alterations to the structure of mammary epithelial tissue. Mammary epithelial cell characterization, by immunohistochemistry approach, revealed a persistence of virgin markers which sign a delay in their differentiation. Moreover serial transplantation experiments show that Rspo1 is associated with a regenerative potential of mammary epithelial cell control. Our data have also highlighted that in mammary gland during pregnancy the expression of Rspo1’s partners, Lgr4 and RNF43, are negatively regulated and Tgf-β signaling is modified in the absence of Rspo1. Taken together, our results show an abrupt halt in mammary development at mid-pregnancy due to loss of further differentiated function.

ORGANISM(S): Mus musculus

PROVIDER: GSE81244 | GEO | 2017/02/09

SECONDARY ACCESSION(S): PRJNA321036

REPOSITORIES: GEO

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Mus musculus

Project description:Rspo1 role in mammary gland during pregnancy

| PRJNA321036 | ENA

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Project description:The mammary gland develops mainly postnatally, when during pregnancy the epithelium grows out into the mammary fat pad and forms a network of epithelial ducts. During pregnancy, these ducts branch and bud to form alveoli. These alveoli produce the milk during lactation. After 7 days of lactation, involution was induced by force weaning the pups. The newly formed epithelium undergoes apoptosis and is removed from the tissue by neighbouring epithelial cells. Tissue remodelling leads to a morphology resembling a gland of a pre-pregnant mouse. Microarray analysis was used to measure mRNA expression of genes during puberty, pregnancy, lactation and involution in a Balb/c mouse strain. Keywords: developmental time course

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Single cell changes in RSPO1-Fc treated intestinal adenoma organoids from ApcMin/+ mice

Project description:We constructed AAV-vectors for systemic expression of a soluble RSPO1 protein in ApcMin/+ mice. We found that the RSPO1-Fc fusion protein suppresses the Wnt/ß-catenin signaling activity in intestinal adenomas and in adenoma-derived intestinal organoids ex vivo, but not in normal intestinal epithelial cells. In the Apc mutant cells, the RSPO1-Fc fusion protein activated the TGFß/SMAD signaling pathway to suppress several Wnt target genes and adenoma growth, which effect was rescued suppressed by the TGFß receptor kinase inhibitor SB-431542. Simultaneously, RSPO1-Fc induced proliferation of the normal intestinal stem cells, giving them a growth advantage over the mutant cells, which enabled the intestinal epithelium to eventually outgrow the adenoma cells. Prolonged systemic expression of AAV-RSPO1-Fc decreased significantly the number of the intestinal adenomas and improved the overall survival of ApcMin/+ mice. Thus RSPO1-Fc provides the normal intestinal epithelial cells a growth advantage when compared to the adenoma cells, which eventually leads to the extrusion of the adenomatous tissue. An attractive idea now is to exploit such differential response of normal vs. cancer cells in cancer therapy.

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Single cell changes in AAV-Ctrl or AAV-RSPO1-Fc treated intestinal adenoma cells from ApcMin/+ mice

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microRNA expression during ovine adult mammary gland development

Project description:The mammary gland undergoes extensive remodeling between the begin- ning of pregnancy and lactation; this involves cellular processes including cell proliferation, differentiation, and apoptosis, all of which are under the control of numerous regulators. To unravel the role played by miRNA, we describe here 47 new ovine miRNA cloned from mammary gland in early pregnancy displaying strong similari- ties with those already identified in the cow, human, or mouse. A microarray study of miRNA variations in the adult ovine mammary gland during pregnancy and lactation showed that 100 miRNA are regulated according to three principal patterns of expression: a de- crease in early pregnancy, a peak at midpregnancy, or an increase throughout late pregnancy and lactation. One miRNA displaying each pattern (miR-21, miR-205, and miR-200b) was analyzed by qRT- PCR. Variations in expression were confirmed for all three miRNA. Using in situ hybridization, we detected both miR-21 and miR-200 in luminal mammary epithelial cells when expressed, whereas miR-205 was expressed in basal cells during the first half of pregnancy and then in luminal cells during the second half. We therefore conclude that miR-21 is strongly expressed in the luminal cells of the normal mammary gland during early pregnancy when extensive cell prolif- eration occurs. In addition, we show that miR-205 and miR-200 are coexpressed in luminal cells, but only during the second half of pregnancy. These two miRNA may cooperate to maintain epithelial status by repressing an EMT-like program, to achieve and preserve the secretory phenotype of mammary epithelial cells. 5 samples for sheep and 5 samples for mouse

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RNA-seq analysis of FET cells treated with RSPO1 or TGFβ1

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AP-2γ is Required for Maintenance of Multipotent Mammary Stem Cells

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2020-12-30 | GSE143159 | GEO

Genome-wide transcriptional effects of Pregnancy-Induced Non-coding RNA (PINC)

Project description:Pregnancy-Induced Non-Coding RNA (PINC) is upregulated in alveolar cells of the mammary gland during pregnancy and persist in alveolar cells that remain in the regressed lobules following involution. Here, we show that in the post-pubertal mouse mammary gland, mPINC expression increases throughout pregnancy and then declines in early lactation, when alveolar cells undergo terminal differentiation. Accordingly, mPINC expression is significantly decreased when HC11 mammary epithelial cells are induced to differentiate and produce milk proteins. This natural reduction in mPINC levels may be necessary for lactation, as overexpression of mPINC in HC11 cells blocks lactogenic differentiation, while knockdown of mPINC enhances differentiation. HC11 mammary epithelial cells, with or without knockdown or over-expression of PINC, and with or without treatment by differentiation-inducing agents, were profiled for gene expression.

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