be predicted to result in gross disruption of the gene product, which is an important participant in cell-to-cell signaling during morphogenesis.
How is the human Jagl protein involved in cell differentiation, and, thereby, in Alagille syndrome? The answer lies in another protein, termed Notch, 9 which was defined in Drosophila melanogaster and is named for the shape of the wings of flies with only one functional copy of the Notch gene. Notch protein is a transmembrane receptor. It is synthesized in the embryo as originally ''equivalent'' cells become committed to particular lineages. The Notch gene is expressed at many sites and at many stages of development. (Other organisms have genes for homologues of Notch; humans are known at present to synthesize three Notch-like proteins in embryonic tissues, in normally proliferating regions of mature tissues, and, interestingly, in certain ''precancerous'' and malignant lesions.) Activated Notch and Notchlike proteins appear to interact with a variety of cytoplasmic and nuclear proteins affecting both transcription and translation, as might be expected of gene products that mediate cell differentiation. Activation of Notch occurs through binding of the ligands Delta and Serrate, which are extracellular, membrane-anchored proteins. Rat homologues of Serrate are called Jagged1 and Jagged2. The rat Jagged1 gene is expressed at sites involved by the malformations of Alagille syndrome; Jag1, then, can be inferred to act as a ligand for Notch-like proteins during human development. Deficiency of Jag1 may well disrupt normal morphogenesis by impeding activation of Notch-like proteins, and the resultant lesions can be those of Alagille syndrome.
As persons in whom a copy of Jag1 is deleted (as shown by karyotypic studies) and persons in whom a copy of Jag1 is disrupted (as shown by mutational analysis) have similar phenotypes, it seems that haploinsufficiency, or absence of adequate supplies of gene product, rather than perturbations caused by a mutant protein, is responsible for the malformations of Alagille syndrome. But other factors, both in the Notch signaling pathway and distinct from it, must be considered in tracing the effects of Jag1 deficiency, because persons with the same Jag1 mutations-parent and child, sibling and sibling-often have different phenotypes. It may be that mutation analysis alone will be of limited use in understanding how lesions caused by Jag1 deficiency arise.
Mutation analysis will be essential, however, in answering questions that could not be posed until now. It seems that not all persons with mutations in Jag1 have classically defined Alagille syndrome. On the other side of the coin, do all persons with the ''Alagille phenotype'' necessarily have mutations in Jag1? Perhaps it can be predicted that defects in the receptor, rather than the ligand, occasionally will generate an ''Alagille phenocopy.'' Such defects can only be identified when instances of clinically defined Alagille syndrome are evaluated through mutation analysis at Jag1. Such a mutation analysis should also be considered in evaluation of a variety of disorders other than classic Alagille syndrome. All the mutations in Jag1 defined to date have been in materials from persons or families rigorously selected for bile duct paucity and cholestasis, and all are predicted to result in severe disruption of the synthesis or structure of Jag1. Is it possible that certain types of Jag1 mutations will prove to underlie nonsyndromic bile duct paucity without cardiac, ocular, or skeletal lesions? What classes of mutations in Jag1 will be found in persons whose clinical disorder is dominated by cardiac or ocular findings, when, for example, a series of infants with tetralogy of Fallot is screened?
Genetic studies in liver disease offer insight not only into hepatic physiology 1-4 but also into mechanisms of hepatobiliary development, and, as in Alagille syndrome, into the development of a restricted but diverse palette of other organs. It will be fascinating to learn why some but not other organ systems are affected by Jag1 mutations. Studies like the ones highlighted here thus permit our understanding of the organism as a whole to take flight-on notched wings.