Cardiopulmonary malformations in the inv/inv mouse

The inv/inv mouse carries an insertional mutation in the inversin gene, (in v, for inversion of embryonic turning). Previously it had been reported tha t almost 100% of the homozygous offspring (inv/inu) were characterized by s itus inversus totalis. In this report we identify the spectrum of cardiopul monary anatomical abnormalities in inv/inu mice surviving to birth to deter mine whether the abnormalities seen are of the categories classically assoc iated with human situs abnormalities. Stillborn mice, offspring that died u nexpectedly (within 48 hr after birth), and neonates with phenotypic charac teristics of situs inversus (right-sided stomachs, growth failure or jaundi ce) were processed for standard histological examination. Of 173 offspring, 34 (20%) neonates (11 stillborn, 9 unexpected deaths, and 14 mice with sit us inversus phenotype) were examined, 27 of which were genotyped to be inv/ inv. Interestingly, three inv/inv mice (11%) were found to have situs solit us. Twenty-four had situs inversus with normal, mirror-image cardiac anatom y (dextrocardia with atrioventricular concordance, ventriculoarterial conco rdance and a right aortic arch). The overall incidence of cardiovascular an omalies observed was 10 out of 27 (37%). The most frequent severe malformat ion, identified in 3 out of 27 animals, was a complex consisting of pulmona ry infundibular stenosis/atresia with absence of pulmonary valve tissue and a ventricular septal defect. The pulmonary phenotype in inv/inv mice was s itus 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/in v mice have a propensity for defects in the development of the right ventri cular outflow tract and the interventricular septum, and 3) approximately o ne out of ten inv/inv mice is born with situs solitus and shows cardiac ano malies that correspond to those observed in inv/inv specimens with situs in versus. Our data therefore suggest that inversin, the product of the inv lo cus, may have specific roles in cardiac morphogenesis independent of its ro le in situs determination. Anat Rec 263:62-71, 2001, (C) 2001 Wiley-Liss, I nc.