JAGGED1 gene expression during human embryogenesis elucidates the wide phenotypic spectrum of Alagille syndrome

Mutations of the JAGGED1 gene, encoding a NOTCH receptor ligand, cause Alag ille syndrome (AGS), a complex malformative disorder affecting mainly the l iver, heart, vertebrae, eye, and face. Minor and occasional features involv ing kidney, pharynx, systemic arteries, skeleton, and ear are in some cases associated with the syndrome. To describe the expression of JAGGED1 during human embryogenesis and to study its relationship with all the features of AGS, we performed in situ hybridization studies on human embryos and fetal tissue sections. JAGGED1 was mainly expressed in the cardiovascular system . In the liver, JAGGED1 transcripts were only detected in blood vessels. JA GGED1 was also expressed in other structures of mesenchymal origin (distal mesenchyme of limb buds; mesonephric and metanephric tubules of the kidney) and in epithelial structures including the ciliary margin of the retina an d the posterior part of the lens, the ventral epithelium of the otic vesicl e, the neurosensory epithelium of the ear vestibule, the epithelium of phar yngeal arches, and the developing central nervous system. The strong JAGGED 1 expression during human embryo- and fete-genesis both in the vascular sys tem and in other mesenchymal and epithelial tissues implicates abnormal ang iogenesis in the pathogenesis of Alagille syndrome and particularly the pau city of interlobular bile ducts. However, it is probably not the only mecha nism of the disease. Except for the central nervous system, there is a stro ng correlation between JAGGED1 expression and all the features of AGS. This implies that the features occasionally associated with the syndrome are no t coincidental.