The goals of this proposal are to investigate the role that Notch2 plays in mammalian organ development and to determine the mechanism behind its influence on heart, kidney, and liver development.
Specific aims 1 and 2 will examine a Notch2 hypomorph by marker and chimera analyses. The significance of this Notch2 allele is that it displays a number of highly penetrant phenotypes at late stages of embryogenesis, thus permitting a.unique opportunity to analyze Notch signaling in different organs and tissue types than those previously studied.
Specific aim 3 proposes the generation of double mutants between Notch2 and its putative ligands to identify ligand receptor pairs, and to identify new Notch related phenotypes.
Specific aim 4 will generate a conditional allele of Jagged1 that will allow the study of Jagged1 function later in development than the null mutation allows. Conditional inactivation will likely lead to the determination of new functions for Jagged1 and allow for further analysis of Jagged1-Notch2 interaction.
Specific aims 3 and 4 may also lead to the generation of a mouse model for Alagille's syndrome; a human congenital disease associated with Jagged1 nonsense mutations.
