GOOSECOID-LIKE (GSCL), A CANDIDATE GENE FOR VELOCARDIOFACIAL SYNDROME, IS NOT ESSENTIAL FOR NORMAL MOUSE DEVELOPMENT

Velocardiofacial syndrome (VCFS) and DiGeorge syndrome (DGS) are chara cterized by a wide spectrum of abnormalities, including conotruncal he art defects, velopharyngeal insufficiency, craniofacial anomalies and learning disabilities, In addition, numerous other clinical features h ave been described, including frequent psychiatric illness. Hemizygosi ty for a 1.5-3 Mb region of chromosome 22q11 has been detected in >80% of VCFS/DGS patients. It is thought that a developmental field defect is responsible for many of the abnormalities seen in these patients a nd that the defect occurs due to reduced levels of a gene product acti ve in early embryonic development. Goosecoid-like (GSCL) is a homeobox gene which is present in the VCFS/DGS commonly deleted region. The mo use homolog, Gscl, is expressed in mouse embryos as early as E8.5. Gsc l is related to Goosecoid (Gsc), a gene required for proper craniofaci al development in mice. GSCL has been considered an excellent candidat e for contributing to the developmental defects in VCFS/DGS patients. To investigate the role of Goosecoid-like in VCFS/DGS etiology, we dis rupted the Gscl gene in mouse embryonic stem cells and produced mice t hat transmit the disrupted allele. Mice that are homozygous for the di srupted allele appear to be normal and they do not exhibit any of the anatomical abnormalities seen in VCFS/DGS patients. RNA in situ hybrid ization to mouse embryo sections revealed that Gscl is expressed at E8 .5 in the rostral region of the foregut and at E11.5 and E12.5 in the developing brain, in the pens region and in the choroid plexus of the fourth ventricle. Although the gene inactivation experiments indicate that haploinsufficiency for GSCL is unlikely to be the sole cause of t he developmental field defect thought to be responsible for many of th e abnormalities in VCFS/DGS patients, its localized expression during development could suggest that hemizygosity for GSCL, in combination w ith hemizygosity for other genes in 22q11, contributes to some of the developmental defects as well as the behavioral anomalies seen in thes e patients. The mice generated in this study should help in evaluating these possibilities.