Dataset Information

Muscle Segment Homeobox Genes Direct Embryonic Diapause by Limiting Inflammation in the Uterus.

ABSTRACT: Embryonic diapause is a reproductive strategy widespread in the animal kingdom. This phenomenon is defined by a temporary arrest in blastocyst growth and metabolic activity within a quiescent uterus without implantation until the environmental and maternal milieu become favorable for pregnancy to progress. We found that uterine Msx expression persists during diapause across species; their inactivation in the mouse uterus results in termination of diapause with the development of implantation-like responses ("pseudoimplantation") that ultimately succumbed to resorption. To understand the cause of this failure, we compared proteome profiles between floxed and Msx-deleted uteri. In deleted uteri, several functional networks, including transcription/translation, ubiquitin-proteasome, inflammation, and endoplasmic reticulum stress, were dysregulated. Computational modeling predicted intersection of these pathways on an enhanced inflammatory signature. Further studies showed that this signature was reflected in increased phosphorylated I?B levels and nuclear NF?B in deleted uteri. This was associated with enhanced proteasome activity and endoplasmic reticulum stress. Interestingly, treatment with anti-inflammatory glucocorticoid (dexamethasone) reduced the inflammatory signature with improvement of the diapause phenotype. These findings highlight an unexpected role of uterine Msx in limiting aberrant inflammatory responses to maintain embryonic diapause.

SUBMITTER: Cha J

PROVIDER: S-EPMC4463472 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Muscle Segment Homeobox Genes Direct Embryonic Diapause by Limiting Inflammation in the Uterus.

Cha Jeeyeon J Burnum-Johnson Kristin E KE Bartos Amanda A Li Yingju Y Baker Erin S ES Tilton Susan C SC Webb-Robertson Bobbie-Jo M BJ Piehowski Paul D PD Monroe Matthew E ME Jegga Anil G AG Murata Shigeo S Hirota Yasushi Y Dey Sudhansu K SK

The Journal of biological chemistry 20150430 24

Embryonic diapause is a reproductive strategy widespread in the animal kingdom. This phenomenon is defined by a temporary arrest in blastocyst growth and metabolic activity within a quiescent uterus without implantation until the environmental and maternal milieu become favorable for pregnancy to progress. We found that uterine Msx expression persists during diapause across species; their inactivation in the mouse uterus results in termination of diapause with the development of implantation-lik ...[more]

PMID: 25931120

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Project description:IntroductionThe homeobox-containing transcription factor muscle segment homeobox 2 (Msx2) plays an important role in mammary gland development. However, the clinical implications of Msx2 expression in breast cancer are unclear. The aims of this study were to investigate the potential clinical value of Msx2 as a breast cancer biomarker and to clarify its functional role in vitro.MethodsMsx2 gene expression was first examined in a well-validated breast cancer transcriptomic dataset of 295 patients. Msx2 protein expression was then evaluated by immunohistochemistry in a tissue microarray (TMA) containing 281 invasive breast tumours. Finally, to assess the functional role of Msx2 in vitro, Msx2 was ectopically expressed in a highly invasive breast tumour cell line (MDA-MB-231) and an immortalised breast cell line (MCF10a), and these cell lines were examined for changes in growth rate, cell death and cell signalling.ResultsExamination of Msx2 mRNA expression in a breast cancer transcriptomic dataset demonstrated that increased levels of Msx2 were associated with good prognosis (P = 0.011). Evaluation of Msx2 protein expression on a TMA revealed that Msx2 was detectable in both tumour cell nuclei and cytoplasm. Cytoplasmic Msx2 expression was associated with low grade tumours (P = 0.012) and Ki67 negativity (P = 0.018). Nuclear Msx2 correlated with low-grade tumours (P = 0.015), estrogen receptor positivity (P = 0.038), low Ki67 (P = 0.005) and high cyclin D1 expression (P = 0.037). Increased cytoplasmic Msx2 expression was associated with a prolonged breast cancer-specific survival (P = 0.049), recurrence-free survival (P = 0.029) and overall survival (P = 0.019). Ectopic expression of Msx2 in breast cell lines resulted in radically decreased cell viability mediated by induction of cell death via apoptosis. Further analysis of Msx2-expressing cells revealed increased levels of p21 and phosphorylated extracellular signal-regulated kinase (ERK) and decreased levels of Survivin and the 'split ends' (SPEN) protein family member RBM15.ConclusionsWe conclude that increased Msx2 expression results in improved outcome for breast cancer patients, possibly by increasing the likelihood of tumour cell death by apoptosis.

Project description:The most common ladybird beetle, Coccinella septempunctata L., is an excellent predator of crop pests such as aphids and white flies, and it shows a wide range of adaptability, a large appetite and a high reproductive ability. Diapause research plays an important role in the artificial propagation and shelf-life extension of insect products. Although this lady beetle's regulatory, physiological and biochemical characteristics in the diapause period are well understood, the molecular mechanism of diapause remains unknown. Therefore, we collected female adults in three different states, i.e., non-diapause, diapause and diapause termination, for transcriptome sequencing.After transcriptome sequencing using the Illumina HiSeq 2500 platform with pretreatment, a total of 417.6 million clean reads from nine samples were filtered using the program FASTX (version 0.0). Additionally, 106,262 contigs were assembled into 82,820 unigenes with an average length of 921 bp and an N50 of 1,241 bp. All of the unigenes were annotated through BLASTX alignment against the Nr or UniProt database, and 37,872 unigenes were matched. We performed further analysis of these unigenes using the Clusters of Orthologous Groups of proteins (COG), Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Through pairwise comparisons of the non-diapause (ND), diapause (D), and diapause-terminated (DT) groups, 3,501 and 1,427 differentially expressed genes (DEGs) were identified between D and ND and between DT and D, respectively. Moreover, 443 of the DEGs were specifically expressed during the diapause period (i.e., DEGs that were expressed at the highest or lowest levels during diapause compared with the other stages). GO function and KEGG pathway enrichment were performed on all DEGs and showed that RNA-directed DNA polymerase activity and fatty acid metabolism were significantly affected. Furthermore, eight specific expressed genes were selected for validation using qRT-PCR. Among these eight genes, seven genes were up-regulated, and one gene was down-regulated; the change trends of the eight genes were the same between the qRT-PCR and RNA-seq analysis results.In this study, a new method for collecting and identifying diapause insects was described. We generated a vast quantity of transcriptome data from C. septempunctata L., providing a resource for gene function research. The diapause-associated genes that we identified establish a foundation for future studies on the molecular mechanisms of diapause.

Dataset Information

Muscle Segment Homeobox Genes Direct Embryonic Diapause by Limiting Inflammation in the Uterus.

Publications

Muscle Segment Homeobox Genes Direct Embryonic Diapause by Limiting Inflammation in the Uterus.

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