RGD Reference Report - Gene Expression of FRAS1-Related Extracellular Matrix 1 Is Decreased in Nitrofen-Induced Congenital Diaphragmatic Hernia. - Rat Genome Database
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Gene Expression of FRAS1-Related Extracellular Matrix 1 Is Decreased in Nitrofen-Induced Congenital Diaphragmatic Hernia.

Authors: Takahashi, T  Friedmacher, F  Puri, P 
Citation: Takahashi T, etal., Eur J Pediatr Surg. 2016 Feb;26(1):81-5. doi: 10.1055/s-0035-1559884. Epub 2015 Sep 18.
RGD ID: 11554195
Pubmed: (View Article at PubMed) PMID:26382659
DOI: Full-text: DOI:10.1055/s-0035-1559884

INTRODUCTION: The origin of congenital diaphragmatic hernia (CDH) is considered to lie in a malformation of the nonmuscular primordial diaphragm. It is known that fetal diaphragmatic development requires the structural integrity of its underlying mesenchymal tissue. Developmental mutations that inhibit the formation of normal diaphragmatic mesenchyme have been shown to cause CDH. FRAS1-related extracellular matrix 1 (FREM1) plays a critical role in the development of the fetal diaphragm. It has been demonstrated that a deficiency of FREM1 can lead to CDH both in humans and mice. Furthermore, FREM1-deficient fetuses exhibit a decreased level of mesenchymal cell proliferation in their developing diaphragms. We hypothesized that FREM1 expression is decreased in developing diaphragms of fetal rats with nitrofen-induced CDH. MATERIAL AND METHODS: Timed-pregnant rats were exposed to either nitrofen or vehicle on gestational day 9 (D9), and fetuses were harvested on selected time-points D13, D15, and D18. Dissected diaphragms (n = 72) were divided into control and nitrofen-exposed samples (n = 12 per time-point and experimental group). Diaphragmatic gene expression levels of FREM1 were analyzed by quantitative polymerase chain reaction. Immunofluorescence staining for FREM1 was combined with the mesenchymal marker GATA4 to localize FREM1 protein expression and tissue distribution in fetal diaphragms. RESULTS: In nitrofen-exposed fetuses, relative mRNA expression of FREM1 was significantly reduced in pleuroperitoneal folds on D13 (0.30 +/- 0.23 vs. 0.83 +/- 0.19; p < 0.05), developing diaphragms on D15 (0.54 +/- 0.22 vs. 1.19 +/- 0.28; p < .05) and fully muscularized diaphragms on D18 (0.49 +/- 0.37 vs. 0.97 +/- 0.53; p < 0.05) in comparison with controls. Confocal laser scanning microscopy revealed markedly diminished diaphragmatic FREM1 immunofluorescence, which was associated with reduced proliferation of diaphragmatic mesenchymal cells in nitrofen-exposed fetuses on D13, D15, and D18 compared to controls. CONCLUSIONS: Decreased expression of FREM1 in the nitrofen-induced CDH model may disturb the formation of the diaphragmatic mesenchyme, thus contributing to the development of diaphragmatic defects.


Disease Annotations    

Objects Annotated

Genes (Rattus norvegicus)
Frem1  (Fras1 related extracellular matrix 1)

Genes (Mus musculus)
Frem1  (Fras1 related extracellular matrix protein 1)

Genes (Homo sapiens)
FREM1  (FRAS1 related extracellular matrix 1)

Additional Information