Per2 regulation of mammary gland development and branching morphogenesis via cell fate determination
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA431294 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6503928.fastq.gz | Fastqsanger.gz | |||
| SRR6503929.fastq.gz | Fastqsanger.gz |
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Project description:Circadian rhythms play key roles in daily physiological functions, development, and cancer. Period 2 (PER2) is a repressive element which inhibits transcription activated by positive clock elements resulting in diurnal cycling of genes. Here we show, that outside of time keeping, PER2 has a non-circadian function that is critical to mammary gland development. Virgin Per2 deficient mice, Per2ldc, have underdeveloped glands containing fewer bifurcations and terminal ducts. Using a transplantation model, we show that these changes are intrinsic to the gland and furthermore identify changes in cell fate commitment. Per2ldc mouse mammary glands have a luminal/basal bi-potent phenotype in cells of the ductal epithelium. We identified co-localization of E-cadherin and Keratin 14 in luminal cells and decreased p63 staining and gene expression in myoepithelial cells. Moreover, Per2ldc mice overexpress SLUG, which is related to mammary stem cell maintenance and EMT. Similar results were demonstrated using MCF10A and shPER2 MCF10A cell lines. Collectively this study reveals a critical non-circadian function of PER2 in mammary gland development, validates the Per2ldc model, and describes a potential role for PER2 in breast cancer.
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Project description:Branching morphogenesis of the mammary gland is driven by the highly motile terminal end bud (TEB) throughout pubertal development. The stem cell enriched, proliferative TEB branches as it invades the mammary fat pad to create a complex network of ducts. The gene expression programs specific to the TEB and the differentiated duct are poorly understood. We conducted a time course analysis of gene expression in the TEB and duct throughout branching morphogenesis. Additionally, we determined the gene regulatory networks coordinated by the Co-factor of LIM domains (CLIM/LDB) transcriptional regulators and determined an essential function for CLIMs in branching morphogenesis by maintaining basal mammary epithelial stem cells and promoting cell proliferation. We used laser capture microdissection to isolate TEB and duct cells throughout branching morphogenesis. We then profiled gene expression in these cells to determine gene regulatory networks involved in branching morphogenesis, and specifically those regulated by CLIM transcriptional regulators. Mouse mammary glands from 4, 6, 8, and 10 week old mice (early puberty through early adulthood) were used for laser capture microdissection of TEB and duct cells from WT and K14-DN-Clim transgenic mice. RNA was isolated (Qiagen) and hybridized to Affymetrix MouseGene 1.0 ST arrays. In addition, basal (CD29HiCD24+Lin-) and Luminal (CD29LoCD24+Lin-) cells were sorted and RNA collected for hybridization to Affymetrix MouseGene 1.0ST arrays.
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Project description:Branching morphogenesis of the mammary gland is driven by the highly motile terminal end bud (TEB) throughout pubertal development. The stem cell enriched, proliferative TEB branches as it invades the mammary fat pad to create a complex network of ducts. The gene expression programs specific to the TEB and the differentiated duct are poorly understood. We conducted a time course analysis of gene expression in the TEB and duct throughout branching morphogenesis. Additionally, we determined the gene regulatory networks coordinated by the Co-factor of LIM domains (CLIM/LDB) transcriptional regulators and determined an essential function for CLIMs in branching morphogenesis by maintaining basal mammary epithelial stem cells and promoting cell proliferation. We used laser capture microdissection to isolate TEB and duct cells throughout branching morphogenesis. We then profiled gene expression in these cells to determine gene regulatory networks involved in branching morphogenesis, and specifically those regulated by CLIM transcriptional regulators.
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