Abstract
Background: Duodenal atresia (DA) is a congenital obstruction of the duodenum, which affects 1 in 7000 pregnancies and requires major surgery in the 1st days of life. Three morphological DA types are described. In humans, the association between DA and Down syndrome suggests an underlying, albeit elusive, genetic etiology. In mice, interruption of fibroblast growth factor 10 (Fgf10) gene signaling results in DA in 30–50% of embryos, supporting a genetic etiology. This study aims to validate the spectrum of DA in two novel strains of Fgf10 knock-out mice, in preparation for future and translational research.Methods: Two novel CRISPR Fgf10 knock-out mouse strains were derived and embryos generated by heterozygous plug-mating. E15.5–E19.5 embryos were genotyped with respect to Fgf10 and micro-dissected to determine the presence and type of DA.Results: One twenty seven embryos (32 wild-type, 34 heterozygous, 61 null) were analyzed. No wild-type or heterozygous embryos had DA. However, 74% of Fgf10 null embryos had DA (49% type 1, 18% type 2, and 33% type 3).Conclusion: Our CRISPR-derived strains showed higher penetrance of DA due to single-gene deletion of Fgf10 in mice than previously reported. Further, the DA type distribution in these mice more closely reiterated that observed in humans. Future experiments will document RNA and protein expression of FGF10 and its key downstream signaling targets in normal and atretic duodenum. This includes exploitation of modern, high-fidelity developmental tools, e.g., Fgf10flox/+–tomatoflox/flox mice.
Highlights
Duodenal atresia (DA) is an important congenital cause of bowel obstruction in newborns
Clinical reports have suggested a genetic basis for DA, with an autosomal recessive inheritance pattern reported for some cases (Berant and Kahana, 1970; Gross et al, 1996; Lambrecht and Kluth, 1998), and the well-recognized association with Down syndrome (Trisomy 21), which occurs in approximately one fifth of DA cases (Khan et al, 2017)
We report here our experiences with an fibroblast growth factor 10 (Fgf10) knock-out mouse model, the strains for which were developed using novel CRISPR/Cas9 techniques
Summary
Duodenal atresia (DA) is an important congenital cause of bowel obstruction in newborns. In 1900, the Viennese anatomist Julius Tandler meticulously studied 11 human embryos with apparently normal gut, and theorized that the duodenum underwent a normal “solid cord” phase during development, secondary to exuberant endodermal (epithelial) growth. He suggested failure of this proposed cord to re-canalize accounted for DA (Tandler, 1900). Duodenal atresia (DA) is a congenital obstruction of the duodenum, which affects 1 in 7000 pregnancies and requires major surgery in the 1st days of life. This study aims to validate the spectrum of DA in two novel strains of Fgf knock-out mice, in preparation for future and translational research
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