FUNCTIONAL-ANALYSIS OF GSCL IN THE PATHOGENESIS OF THE DIGEORGE AND VELOCARDIOFACIAL SYNDROMES

Gscl encodes a Goosecoid-related homeodomain protein that is expressed during mouse embryogenesis. in situ hybridization and immunohistochem istry studies show that Gscl is expressed in the pens region of the de veloping central nervous system and primordial germ cells. Gscl expres sion is also detected in a subset of adult tissues, including brain, e ye, thymus, thyroid region, stomach, bladder and testis. Gscl is locat ed within a region of the mouse genome that is syntenic with the regio n commonly deleted in DiGeorge and velocardiofacial syndrome (DGS/VCFS ) patients, DGS/VCFS patients have craniofacial abnormalities, cardiac outflow defects and hypoplasia of the parathyroid grand and thymus du e to haploinsufficiency of a gene or genes located within the deleted region. Thus, the genomic location of Gscl and its expression in a sub set of the tissues affected in DGS/VCFS patients suggest that Gscl may contribute to the pathogenesis of DGS/VCFS. To determine the role of Gscl during mouse embryogenesis and in DGS/VCFS, we have deleted Gscl by gene targeting in mouse embryonic stem cells. Both Gscl heterozygou s and Gscl null mice were normal and fertile, suggesting that Gscl is not a major factor in DGS/VCFS. Interestingly, expression of the adjac ent Es2 gene in the pens region of Gscl null fetuses was absent, sugge sting that mutations within the DGS/VCFS region can influence expressi on of adjacent genes. In addition, embryos that lacked both Gscl and t he related Gsc gene appeared normal, These studies represent the first functional analysis of a DGS/VCFS candidate gene in vivo. These Gscl null mice will be an important genetic resource for crosses with other mouse models of the DGS/VCFS.