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Molecular and Cellular Biology, March 2001, p. 1475-1483, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1475-1483.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Craniofacial Dysmorphogenesis Including Cleft Palate in Mice with an Insertional Mutation in the discs large Gene

Georgina Caruana1,* and Alan Bernstein1,2,3

Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5,1 Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5S 1A1,2 and Canadian Institutes of Health Research, Ottawa, Ontario K1A 0W9,3 Canada

Received 19 September 2000/Returned for modification 30 October 2000/Accepted 28 November 2000

The discs large (Dlg) 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 dlg is the homologue of the Drosophila dlg tumor suppressor gene. The loss of dlg function in Drosophila disrupts cellular growth control, apicobasal polarity, and cell adhesion of imaginal disc epithelial cells, resulting in embryonic lethality. In this study, we isolated a mutational insertion in the murine dlg locus by gene trapping in totipotent embryonic stem cells. This insertion results in a truncated protein product that contains the N-terminal three PSD-95/DLG/ZO-1 domains of Dlg fused to the LacZ reporter and subsequently lacks the src homology 3 (SH3), protein 4.1 binding, and guanylate kinase (GUK)-like domains. The Dlg-LacZ fusion protein is expressed in epithelial, mesenchymal, neuronal, endothelial, and hematopoietic cells during embryogenesis. Mice homozygous for the dlg mutation exhibit growth retardation in utero, have hypoplasia of the premaxilla and mandible, have a cleft secondary palate, and die perinatally. Consistent with this phenotype, Dlg-LacZ is expressed in mesenchymal and epithelial cells throughout palatal development. Our genetic and phenotypic analysis of dlg mutant mice suggests that protein-protein interactions involving the SH3, protein 4.1 binding, and/or GUK-like domains are essential to the normal function of murine Dlg within craniofacial and palatal morphogenesis.

* Corresponding author. Present address: Department of Anatomy and Cell Biology, Monash University, Clayton Campus, Bldg. 13C, West Ring Rd., Victoria 3168, Australia. Phone: 61-3-9905-2751. Fax: 61-3-9905-2766. E-mail: g.caruana{at}med.monash.edu.au.

Molecular and Cellular Biology, March 2001, p. 1475-1483, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1475-1483.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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