To understand the functional role of peroxisomal membrane channel Pxmp2, mice with a targeted disruption of the Pxmp2 gene were developed. These mice were viable, grew and bred normally. However, Pxmp2-/- were unable to nurse their pups due to retarded mammary ductal outgrowth associated with reduced proliferation of epithelial cells during puberty. Transplantation experiments established the Pxmp2-/- mammary stroma as a tissue responsible for suppression of epithelial growth. Morphological and biochemical examination revealed the presence of peroxisomes in mammary adipocytes, and functional Pxmp2 was detected in the stroma of WT mice. Comparative microarray analysis of WT and Pxmp2-/- mammary fat pad identified an expanded set of differentially expressed genes involved in the regulation of epithelial development. The data point to the possible role of lipid-sensing receptors in mechanisms linking Pxmp2 deficiency and suppression of mammary epithelial growth. The hypothesis was verified using the PPAR agonist clofibrate, which was able to avert pubertal development of mammary epithelium in WT mice. However, treatment of Pxmp2-/- mice with PPAR antagonist MK886 could only partially restore epithelial growth suggesting that several lipid-sensing or other receptors may be affected by Pxmp2 deficiency. The data reveal impaired mammary gland development as a new category of peroxisomal disorders.
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Sex
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Sex, Specimen part
View SamplesWnt-4 signaling is critical for embryonic female sexual development. When Wnt-4 gene is deleted during embryonic development, the knock-out females present a partial sex reversal.
Identification of the genes regulated by Wnt-4, a critical signal for commitment of the ovary.
Specimen part
View SamplesThree-dimensional (3D) organoids provide a new way to model various diseases, including cancer. We made use of recently developed kidney-organ-primordia tissue-engineering technologies to create novel renal organoids for cancer gene discovery. We then tested whether our novel assays can be used to examine kidney cancer development. First, we identified the transcriptomic profiles of quiescent embryonic mouse metanephric mesenchyme (MM) and of MM in which the nephrogenesis program had been induced ex vivo. The transcriptome profiles were then compared to the profiles of tumor biopsies from renal cell carcinoma (RCC) patients, and control samples from the same kidneys. Certain signature genes were identified that correlated in the developmentally induced MM and RCC, including components of the caveolar-mediated endocytosis signaling pathway. An efficient siRNA-mediated knockdown (KD) of Bnip3, Gsn, Lgals3, Pax8, Cav1, Egfr or Itgb2 gene expression was achieved in mouse RCC (Renca) cells. The live-cell imaging analysis revealed inhibition of cell migration and cell viability in the gene-KD Renca cells in comparison to Renca controls. Upon siRNA treatment, the transwell invasion capacity of Renca cells was also inhibited. Finally, we mixed the nephron progenitors with yellow fluorescent protein (YFP)-expressing Renca cells to establish chimera organoids. Strikingly, we found that the Bnip3-, Cav1- and Gsn-KD Renca-YFP+ cells as a chimera with the MM in 3D organoid rescued, in part, the RCC-mediated inhibition of the nephrogenesis program during epithelial tubules formation. Altogether, our research indicates that comparing renal ontogenesis control genes to the genes involved in kidney cancer may provide new growth-associated gene screens and that 3D RCC-MM chimera organoids can serve as a novel model with which to investigate the behavioral roles of cancer cells within the context of emergent complex tissue structures.
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Specimen part
View SamplesThe Hippocampus Consortium data set provides estimates of mRNA expression in the adult hippocampus of 99 genetically diverse strains of mice including 67 BXD recombinant inbred strains, 13 CXB recombinant inbred strains, a diverse set of common inbred strains, and two reciprocal F1 hybrids.
Genetics of the hippocampal transcriptome in mouse: a systematic survey and online neurogenomics resource.
Sex, Age, Specimen part
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Dynamic changes in 5-hydroxymethylation signatures underpin early and late events in drug exposed liver.
Sex, Specimen part, Treatment, Time
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Homer1a is a core brain molecular correlate of sleep loss.
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STAT6 transcription factor is a facilitator of the nuclear receptor PPARγ-regulated gene expression in macrophages and dendritic cells.
Specimen part, Treatment, Subject, Time
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Conserved principles of mammalian transcriptional regulation revealed by RNA half-life.
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View SamplesCopy number variation (CNV) of DNA segments has recently been identified as a major source of genetic diversity, but a more comprehensive understanding of the extent and phenotypic effect of this type of variation is only beginning to emerge. In this study we generated genome-wide expression data from 6 mouse tissues to investigate how CNVs influence gene expression.
Segmental copy number variation shapes tissue transcriptomes.
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