Abstract 370: Mahogunin Ring Finger 1 (Mgrn1) Mutant Mice: A New Model of Left-Right Patterning and Congenital Heart Defects
Congenital heart defects are the most common of all birth defects and a leading cause of infant mortality. Defects in patterning of the left-right body axis commonly lead to a spectrum of heart defects and embryonic death. Over the last decade, mouse mutants have provided great insight into the molecular mechanisms of left-right patterning. The Mahogunin Ring Finger 1 (Mgrn1) gene encodes a widely expressed, evolutionarily conserved RING-containing ubiquitin ligase. Mice lacking MGRN1 have several defects, including dark fur, adult-onset neurodegeneration, and reduced embryonic viability. Approximately 40% of homozygous mutants die by weaning age, many prenatally, and a small proportion (<1%) of adults show complete situs inversus. We hypothesize that MGRN1 is important for establishment and/or maintenance of the left-right axis during development and that loss of MGRN1 leads to random patterning and congenital heart defects, with reduced penetrance. We found that expression of MGRN1 during early embryogenesis was consistent with a role in left-right patterning. It was detected in the node of presomite embryos. At later stages it was expressed more broadly, including in the midline of the floorplate and in the heart. Approximately 30% of Mgrn1 mutant embryos showed obvious misexpression of genes important in left-right patterning, including Lefty1, Lefty2 and Pitx2. By histological analysis, a spectrum of complex heart defects were observed in ~40% of mid-gestation embryos, including septal defects, thinning of the myocardium, malpositioning of the great arteries, retroesophageal left subclavian artery, abnormal heart situs, and/or pericardial effusion. Our results indicate that Mgrn1 acts early in the left-right signaling pathway and is important for normal heart development. The biochemical function of MGRN1 suggests a novel role for ubiquitination in establishing left-right patterning during early embryogenesis.