Craniofacial dysmorphogenesis including cleft palate in mice with an insertional mutation in the discs large gene

The discs large (DIg) protein, or synapse-associated protein 97 (SAP97), is a member of the membrane-associated guanylate kinase family of multidomain scaffolding proteins which recruits transmembrane and signaling molecules to localized plasma membrane sites. Murine dig is the homologue of the Dros ophila dig tumor suppressor gene. The loss of dig function in Drosophila di srupts cellular growth control, apicobasal polarity, and cell adhesion of i maginal disc epithelial cells, resulting in embryonic lethality. In this st udy, we isolated a mutational insertion in the murine dig locus by gene tra pping in totipotent embryonic stem cells. This insertion results in a trunc ated protein product that contains the N-terminal three PSD-95/DLG/ZO-1 dom ains of Dig fused to the LacZ reporter and subsequently lacks the src homol ogy 3 (SH3), protein 4.1 binding, and guanylate kinase (GUK)-like domains. The Dlg-LacZ fusion protein is expressed in epithelial, mesenchymal, neuron al, endothelial, and hematopoietic cells during embryogenesis. Mice homozyg ous for the dig mutation exhibit growth retardation in utero, have hypoplas ia of the premaxilla and mandible? have a cleft secondary palate, and die p erinatally. Consistent with this phenotype, Dlg-LacZ is expressed in mesenc hymal and epithelial cells throughout palatal development. Our genetic and phenotypic analysis of dlg mutant mice suggests that protein-protein intera ctions involving the SH3, protein 4.1 binding, and/or GUK-like domains are essential to the normal function of murine Dig within craniofacial and pala tal morphogenesis.