Rationale: While modulation of the serotonin transporter (5HTT) has shown to be a risk factor for pulmonary arterial hypertension for almost 40 years, there is a lack of in vivo data about the broad molecular effects of pulmonary inhibition of 5HTT. Previous studies have suggested effects on inflammation, proliferation, and vasoconstriction. The goal of this study was to determine which of these were supported by alterations in gene expression in serotonin transporter knockout mice. Methods: Eight week old normoxic mice with a 5-HTT knock-out (5HTT-/-) and their heterozygote(5HTT+/-) or wild-type(5HTT+/+) littermates had right ventricular systolic pressure(RVSP) assessed, lungs collected for RNA, pooled, and used in duplicate in Affymetrix array analysis. Representative genes were confirmed by quantitative RT-PCR and western blot. Results: RVSP was normal in all groups. Only 124 genes were reliably changed between 5HTT-/- and 5HTT+/+ mice. More than half of these were either involved in inflammatory response or muscle function and organization; in addition, some matrix, heme oxygenase, developmental, and energy metabolism genes showed altered expression. Quantitative RT-PCR for examples from each major group confirmed changes seen by array, with an intermediate level in 5HTT+/- mice. Conclusions: These results for the first time show the in vivo effects of 5HTT knockout in lungs, and show that many of the downstream mechanisms suggested by cell culture and ex vivo experiments are also operational in vivo. This suggests that the effect of 5HTT on pulmonary vascular function arises from its impact on several systems, including vasoreactivity, proliferation, and immune function.
Gene expression in lungs of mice lacking the 5-hydroxytryptamine transporter gene.
No sample metadata fields
View SamplesNeuregulin (NRG) signaling through the receptor tyrosine kinase, ERBB3, is required for embryonic development, and dysregulated signaling has been associated with cancer progression. Here, we show that NRG1/ERBB3 signaling inhibits melanocyte (MC) maturation and promotes undifferentiated, migratory and proliferative cellular characteristics. Embryonic analyses demonstrated that initial MC specification and distribution were not dependent on ERBB3 signaling. However NRG1/ERBB3 signaling was both necessary and sufficient to inhibit differentiation of later stages of MC development in culture. Analysis of tissue arrays of human melanoma samples suggests that ERBB3 signaling may also contribute to metastatic progression of melanoma as ERBB3 was phosphorylated in primary tumors compared with nevi or metastatic lesions. Neuregulin 1-treated MCs demonstrated increased proliferation and invasion and altered morphology concomitant with decreased levels of differentiation genes, increased levels of proliferation genes and altered levels of melanoma progression and metastases genes. ERBB3 activation in primary melanomas suggests that NRG1/ERBB3 signaling may contribute to the progression of melanoma from benign nevi to malignancies. We propose that targeting ERBB3 activation and downstream genes identified in this study may provide novel therapeutic interventions for malignant melanoma.
NRG1 / ERBB3 signaling in melanocyte development and melanoma: inhibition of differentiation and promotion of proliferation.
Specimen part
View SamplesLysine methylation of histones is associated with both transcriptionally active chromatin and with silent chromatin, depending on what residue is modified. Histone methyltransferases and demethylases ensure that histone methylations are dynamic and can vary depending on cell cycle- or developmental stage. KDM4A demethylates H3K36me3, a modification enriched in the 3end of active genes. The genomic targets and the role of KDM4 proteins in development remain largely unknown.
Gene regulation by the lysine demethylase KDM4A in Drosophila.
No sample metadata fields
View SamplesThis SuperSeries is composed of the SubSeries listed below.
WNT5A inhibits metastasis and alters splicing of Cd44 in breast cancer cells.
Cell line
View SamplesA highly metastatic breast cancer cell line, 4T1, was used to generate stable Wnt5a expressing and vector only control cells. Cells were generated using lentivirus infection and selection with blasticidin. Expression of Wnt5a was confirmed using western blot. Cell behaviour was characterized. Wnt5a expressing cells exhibited reduced migration in a transwell assay and reduced metastasis in a tail vein injection assay. Growth was not significantly affected.
WNT5A inhibits metastasis and alters splicing of Cd44 in breast cancer cells.
Cell line
View SamplesComparison of laminin binding and laminin non-binding germ cells
Defining the spermatogonial stem cell.
No sample metadata fields
View SamplesRat germ cells
Defining the spermatogonial stem cell.
No sample metadata fields
View SamplesThe genetic changes underlying metastatic melanoma need to be deciphered to develop new and effective therapeutics. Previously, genome-wide microarray analyses of human melanoma identified two reciprocal gene expression programs, that included expression of mRNAs regulated by either transforming growth factor, beta 1 (TGFB1) pathways or microphthalmia-associated transcription factor (MITF)/SRY-box containing gene 10 (SOX10) pathways. We extend this knowledge to include gene expression analyses of 5 additional human melanoma lines, and show that these lines also fall into either TGFB1 or MITF/SOX10 gene expression groups.
Distinct microRNA expression signatures are associated with melanoma subtypes and are regulated by HIF1A.
Cell line
View SamplesUsing RNA-Seq, we compared the transcriptomes of muscle from wild type C57BL/6J or Zp407 transgenic mice. Overall design: Biceps femoris were stored in RNAlater from 5-week-old overnight-fasted male mice. 5 mice were used per group for wild type and Zp407 transgenic mice.
Zinc finger protein 407 overexpression upregulates PPAR target gene expression and improves glucose homeostasis in mice.
Sex, Age, Specimen part, Subject
View SamplesMice expressing a doxycycline-inducible dominant negative BMPR2 transgene expressed only in smooth muscle are activated for one or eight weeks, and compared to transactivator-only mice also fed doxycycline. All mice are 12 weeks of old at sacrifice.
Molecular effects of loss of BMPR2 signaling in smooth muscle in a transgenic mouse model of PAH.
No sample metadata fields
View Samples