Alagille syndrome is an autosomal dominant disorder characterized by developmental abnormalities of the liver, heart, eye, skeleton and kidney. Alagille syndrome is due to haploinsufficiency for the Jaggedl (Jag1) gene, which encodes a ligand for the Notch family of transmembrane receptors. We have developed a mouse model of Alagille syndrome. While mice heterozygous for a targeted Jag1 null allele do not exhibit most phenotypes characteristic of humans with Alagille syndrome, mice doubly heterozygous for Jag1 and Notch2 targeted mutations exhibit multiple defects similar to human Alagille syndrome patients. These defects include bile duct paucity, glomerular defects in the kidneys, and atrial and ventricular septal defects in the heart. We have identified additional double heterozygous genetic interactions between the Jagl mutation and mutations in the Dill and Notchl genes. These interactions demonstrate that Jagl mutant mice could be used in sensitized mutagenesis screens. We also found that naturally occurring genetic modifiers exist in the C3H strain that enhance ear vestibular defects and suppress eye defects that occur in Jag1 heterozygous mice. ? ? We propose three specific aims to identify and characterize genetic modifiers in this system.
The aims of this proposal are to: 1) map the C3H genetic modifiers of Jag1 heterozygous phenotypes in the eye and inner ear, and determine if these modifiers affect the liver or kidney phenotypes of the Jagl/Notch2 Alagille syndrome model; 2) perform a sensitized genetic screen for chemically-induced dominant enhancers of the phenotypes of Jag1 heterozygous mice; 3) perform a sensitized genetic screen for chemically-induced recessive suppressors of the embryonic lethality of Jag1 homozygous mutant mice. These studies will enable us to create more representative mouse models of Alagille syndrome, and should provide insight into the variable phenotypic expression observed in Alagille syndrome patients. ? ?
| Lozier, Julie; McCright, Brent; Gridley, Thomas (2008) Notch signaling regulates bile duct morphogenesis in mice. PLoS One 3:e1851 |
| Kiernan, Amy E; Li, Renhua; Hawes, Norman L et al. (2007) Genetic background modifies inner ear and eye phenotypes of jag1 heterozygous mice. Genetics 177:307-11 |
| Kiernan, Amy E; Xu, Jingxia; Gridley, Thomas (2006) The Notch ligand JAG1 is required for sensory progenitor development in the mammalian inner ear. PLoS Genet 2:e4 |
| Kiernan, Amy E; Cordes, Ralf; Kopan, Raphael et al. (2005) The Notch ligands DLL1 and JAG2 act synergistically to regulate hair cell development in the mammalian inner ear. Development 132:4353-62 |
