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| Status |
Public on Mar 13, 2015 |
| Title |
Gene expression analysis of FACS-isolated mammary stromal cells (Fsp1-expressing) between stromal Gli2 wild type control and stromal Gli2 ablated mice |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
The capacity of stem cells to maintain and regenerate organs is critically dependent on the niche, a complex signaling microenvironment that sustains and regulates stem cell activity. Niche function in the mammary gland must integrate local homeostatic activities with hormonally regulated events, such as pregnancy or the onset of puberty. In the human disorder CPHD (combined pituitary hormone deficiency) breast growth defects at puberty are associated with mutations disrupting the transcription factor, GLI2. Here we find that Gli2 functions in mouse mammary stromal cells to shape a niche signaling program that sustains mammary epithelial stem cells. Ablation of Gli2 in stromal cells thus leads to a disorganized mammary gland, associated with collapse of the niche signaling environment, with a five-fold decrease in functional mammary stem cell activity, and with attenuated response to the mammatrophic hormones estrogen and growth hormone. Consistent with a niche defect, aspects of Gli2-deficient mammary gland architecture can be rescued by local supplementation with IGF and WNT protein signals. Our findings thus identify GLI2 as a critical coordinator of local and hormonal influences on the niche signaling program, and suggest that mammary pathogenesis in CPHD patients results from dysfunction of the mammary epithelial stem cell niche.
We used microarrays to identify gene expression signatures associated with stromal Gli2 expression
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| Overall design |
To identify stromal factors induced by Gli2 activity, we compared gene expression of FACS-isolated Fsp1Cre-marked stromal cells from Gli2∆S or Gli2WT littermates by microarray analysis, and identified genes encoding paracrine factors such as Igf1, Wnt2, Hgf, Fgf7, and Bmp7; we also identified down-regulated genes encoding estrogen receptor (Esr1), growth hormone receptor (Ghr), and other genes typically expressed in stromal cells. Of particular interest among the paracrine factors, WNT signals sustain the activity of MaSCs and in ex vivo culture, and functional inactivation of Igf1 or its epithelially expressed receptor, Igf-1r, both lead to development of hypoplastic mammary glands with terminal end bud abnormalities similar to the defects we observe in Gli2∆S mice. The down-regulation of these genes was confirmed by qRT-PCR of bulk stromal cells from Gli2WT and Gli2∆S mice, and was further quantified by qRT-PCR from single cells
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| Contributor(s) |
Zhao C, Beachy PA |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
Mar 12, 2015 |
| Last update date |
Feb 21, 2018 |
| Contact name |
CHEN ZHAO |
| E-mail(s) |
chenzhao@stanford.edu
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| Phone |
6314878639
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| Organization name |
Stanford University
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| Department |
Biochemistry
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| Lab |
Dr. Philip A. Beachy
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| Street address |
265 Campus Dr.
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| City |
Stanford |
| State/province |
CA |
| ZIP/Postal code |
94305 |
| Country |
USA |
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| Platforms (1) |
| GPL16570 |
[MoGene-2_0-st] Affymetrix Mouse Gene 2.0 ST Array [transcript (gene) version] |
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| Samples (2) |
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| Relations |
| BioProject |
PRJNA278039 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE66820_RAW.tar |
18.9 Mb |
(http)(custom) |
TAR (of CEL, CHP) |
| GSE66820_comparison.txt.gz |
1.4 Mb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
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