Anomalous development of the hepatobiliary system in the inv mouse

Mazziotti, Mark V.; Willis, Lauren K.; Heuckeroth, Robert O.; LaRegina, Marie C.; Swanson, Paul E.; Overbeek, Paul A.; Perlmutter, David H.

doi:10.1002/hep.510300223

Cited by 126 publications

(70 citation statements)

References 53 publications

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“…Inversin also disrupts normal development and function of the kidney in a fashion that is not easily correlated with determination of situs and this similarly suggests an organ-specific requirement for inversin independent of situs determination. It has been proposed, however, that the biliary tract abnormalities in inv/inv mice are situs related and similar in kind to the biliary tract anomalies occasionally seen in human heterotaxies (Mazziotti et al, 1999). The severe infundibular obstruction without detectable valve tissue seen in ϳ10% of our inv/inv pups is a distinctive cardiac malformation of this model not seen in other mouse models of abnormal left-right axis determination or cardiac malformation.…”

Section: Smad5supporting

confidence: 48%

Cardiopulmonary malformations in the inv/inv mouse

et al. 2001

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The inv/inv mouse carries an insertional mutation in the inversin gene, (inv, for inversion of embryonic turning). Previously it had been reported that almost 100% of the homozygous offspring (inv/inv) were characterized by situs inversus totalis. In this report we identify the spectrum of cardiopulmonary anatomical abnormalities in inv/inv mice surviving to birth to determine whether the abnormalities seen are of the categories classically associated with human situs abnormalities. Stillborn mice, offspring that died unexpectedly (within 48 hr after birth), and neonates with phenotypic characteristics of situs inversus (right-sided stomachs, growth failure or jaundice) were processed for standard histological examination. Of 173 offspring, 34 (20%) neonates (11 stillborn, 9 unexpected deaths, and 14 mice with situs inversus phenotype) were examined, 27 of which were genotyped to be inv/inv. Interestingly, three inv/inv mice (11%) were found to have situs solitus. Twenty-four had situs inversus with normal, mirror-image cardiac anatomy (dextrocardia with atrioventricular concordance, ventriculoarterial concordance and a right aortic arch). The overall incidence of cardiovascular anomalies observed was 10 out of 27 (37%). The most frequent severe malformation, identified in 3 out of 27 animals, was a complex consisting of pulmonary infundibular stenosis/atresia with absence of pulmonary valve tissue and a ventricular septal defect. The pulmonary phenotype in inv/inv mice was situs inversus with occasional minor lobar abnormalities. We conclude that 1) cardiopulmonary malformations in inv/inv mice are not rare (37%), 2) the cardiopulmonary malformations observed in inv/inv specimens are not of the spectrum typically associated with human heterotaxia. In particular, inv/inv mice have a propensity for defects in the development of the right ventricular outflow tract and the interventricular septum, and 3) approximately one out of ten inv/inv mice is born with situs solitus and shows cardiac anomalies that correspond to those observed in inv/inv specimens with situs inversus. Our data therefore suggest that inversin, the product of the inv locus, may have specific roles in cardiac morphogenesis independent of its role in situs determination. Anat Key words: inv/inv; congenital heart malformation; outflow tract; situs inversus inversinLooping is the process of lengthening and bending the primitive heart tube. The side to which the heart tube will bend is remarkably preserved through evolution of vertebrates and is genetically determined. One of the consequences of normal looping is the establishment of the correct spatial relationships between the primitive chambers of the folded heart tube. The extent to which the mechanisms that determine situs also determine the looping heart's ability to establish the correct positional relationships of the primitive chambers is not clear. Although cardiac malposition in general is strongly associated with congenital heart disease in humans, situs inversus totalis carries...

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Section: Smad5supporting

confidence: 48%

Cardiopulmonary malformations in the inv/inv mouse

et al. 2001

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“…The existence of such variables is supported by the variable degrees of biliary injury induced by RRV in different mouse strains (12). Furthermore, animal-and patientbased studies implicate specific genes in the pathogenesis of a subgroup of patients with biliary atresia who also display defects in laterality (2,(25)(26)(27). The presence of mutations in laterality genes in patients with extrahepatic malformations, but not consistently in patients who also have biliary atresia (27,28), points to a modifying but not causative role for these genes in disease pathogenesis.…”

Section: Figurementioning

confidence: 98%

Obstruction of extrahepatic bile ducts by lymphocytes is regulated by IFN-γ in experimental biliary atresia

Shivakumar¹,

Campbell²,

Sabla³

et al. 2004

J. Clin. Invest.

192

236

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The etiology and pathogenesis of bile duct obstruction in children with biliary atresia are largely unknown. We have previously reported that, despite phenotypic heterogeneity, genomic signatures of livers from patients display a proinflammatory phenotype. Here, we address the hypothesis that production of IFN-γ is a key pathogenic mechanism of disease using a mouse model of rotavirus-induced biliary atresia. We found that rotavirus infection of neonatal mice has a unique tropism to bile duct cells, and it triggers a hepatobiliary inflammation by IFN-γ-producing CD4 + and CD8 + lymphocytes. The inflammation is tissue specific, resulting in progressive jaundice, growth failure, and greater than 90% mortality due to obstruction of extrahepatic bile ducts. In this model, the genetic loss of IFN-γ did not alter the onset of jaundice, but it remarkably suppressed the tissue-specific targeting of T lymphocytes and completely prevented the inflammatory and fibrosing obstruction of extrahepatic bile ducts. As a consequence, jaundice resolved, and long-term survival improved to greater than 80%. Notably, administration of recombinant IFN-γ led to recurrence of bile duct obstruction following rotavirus infection of IFN-γ-deficient mice. Thus, IFN-γ-driven obstruction of bile ducts is a key pathogenic mechanism of disease and may constitute a therapeutic target to block disease progression in patients with biliary atresia.

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“…The association of anomalies of visceral organ symmetry with BA (the polysplenia or BA splenic malformation syndrome) implies that genes that control normal situs development are also key regulators of normal extrahepatic bile duct development. The initial animal model that suggested this class of genes was that of a recessive insertional mutation in the proximal region of mouse chromosome 4 or complete deletion of the inversion (inv) gene in the mouse (68,69). This mouse model, with laterality defects in abdominal organ placement, also included anomalous development of the hepatobiliary system.…”

Section: Morphogenesis Genes and Biliary Atresiamentioning

confidence: 99%