Novel exomphalos genetic mouse model: The importance of accurate phenotypic classification

Abstract

BackgroundRodent models of abdominal wall defects (AWD) may provide insight into the pathophysiology of these conditions including gut dysfunction in gastroschisis, or pulmonary hypoplasia in exomphalos. Previously, a Scribble mutant mouse model (circletail) was reported to exhibit gastroschisis. We further characterise this AWD in Scribble knockout mice.MethodHomozygous Scrib knockout mice were obtained from heterozygote matings. Fetuses were collected at E17.5–18.5 with intact amniotic membranes. Three mutants and two control fetuses were imaged by in amnio micro-MRI. Remaining fetuses were dissected, photographed and gut length/weight measured. Ileal specimens were stained for interstitial cells of Cajal (ICC), imaged using confocal microscopy and ICC quantified.Results127 fetuses were collected, 15 (12%) exhibited AWD. Microdissection revealed 3 mutants had characteristic exomphalos phenotype with membrane-covered gut/liver herniation into the umbilical cord. A further 12 exhibited extensive AWD, with eviscerated abdominal organs and thin covering membrane (intact or ruptured). Micro-MRI confirmed these phenotypes. Gut was shorter and heavier in AWD group compared to controls but morphology/number of ICC was not different.DiscussionThe Scribble knockout fetus exhibits exomphalos (intact and ruptured), in contrast to the original published phenotype of gastroschisis. Detailed dissection of fetuses is essential ensuring accurate phenotyping and result reporting.

Transgelin-expressing myofibroblasts orchestrate ventral midline closure through TGFβ signalling

“…Our model of VBW closure might provide a logical explanation for the different anatomical configurations seen in different VBW defects. In thoracoabdominoschesis, there is complete absence of any ventral tissue cover, whereas in our and other models of exomphalos a thin ‘sac’ covers the ventral midline ( Brewer and Williams, 2004 ; Carnaghan et al, 2013 ; Dünker and Krieglstein, 2002 ; Eng et al, 2012 ). The anatomy of the defect might reflect the stage of cellular wave failure.…”

“…Abdominal wall defects are common in humans and cause significant morbidity and mortality ( Wilson and Johnson, 2004 ). They show a variety of phenotypic abnormalities that differ not only in their anatomy, but also in their mode of development, organ involvement and short- and long-term outcomes ( Carnaghan et al, 2013 ; Christison-Lagay et al, 2011 ; Gamba and Midrio, 2014 ; Sadler, 2010 ; Sadler and Feldkamp, 2008 ). Little is known about the mechanisms that drive ventral midline closure in mammals.…”

A review of genetic factors underlying craniorachischisis and omphalocele: Inspired by a unique trisomy 18 case

“…A subsequent study in 2013 by Carnaghan et al bred mice to produce homozygous SCRIB offspring and observed the fetuses under microscopy and micro‐MRI. Out of 127 fetuses, 15 (12%) had isolated anterior closure defects while 10 (8%) had concomitant anterior defects and CRN (Carnaghan et al, ). These mice demonstrated two phenotypes of anterior closure defects: exomphalos of bowel and liver ( n = 3) and complete externalization of all abdominal viscera ( n = 12).…”

Dermatan sulfate epimerase 1 deficient mice as a model for human abdominal wall defects

“…However, it is hard to compare the different suggested models of GS because the described features are very diverse (Carnaghan et al, 2013 ). Phenotypically, most of the existing mouse models seem to be a mixture of OC and GS, including mice deficient in Scrib (Carnaghan et al, 2013 ; Murdoch et al, 2003 ), Aebp1 (Layne et al, 2001 ; Danzer et al, 2010 ), Bmp1 (Suzuki et al, 1996 ), and Tfap2a (Brewer and Williams, 2004b ) (description summarized in Table 3 ). Our mouse model also showed features of both conditions, but the location of the defect was that of an OC.…”