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A direct functional link between the multi-PDZ domain protein GRIP1 and the Fraser syndrome protein Fras1

Nature Genetics volume 36, pages 172–177 (2004)Cite this article

Abstract

Cell adhesion to extracellular matrix (ECM) proteins is crucial for the structural integrity of tissues and epithelial-mesenchymal interactions mediating organ morphogenesis1,2. Here we describe how the loss of a cytoplasmic multi-PDZ scaffolding protein, glutamate receptor interacting protein 1 (GRIP1), leads to the formation of subepidermal hemorrhagic blisters, renal agenesis, syndactyly or polydactyly and permanent fusion of eyelids (cryptophthalmos). Similar malformations are characteristic of individuals with Fraser syndrome and animal models of this human genetic disorder, such as mice carrying the blebbed mutation (bl) in the gene encoding the Fras1 ECM protein3,4. GRIP1 can physically interact with Fras1 and is required for the localization of Fras1 to the basal side of cells. In one animal model of Fraser syndrome, the eye-blebs (eb) mouse, Grip1 is disrupted by a deletion of two coding exons. Our data indicate that GRIP1 is required for normal cell-matrix interactions during early embryonic development and that inactivation of Grip1 causes Fraser syndrome–like defects in mice.

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Figure 1: Grip1 mutants phenocopy mice lacking the Fraser syndrome protein Fras1.
Figure 2: Loss of Grip1 leads to renal agenesis.
Figure 3: The tissue distributions of GRIP1 and Fras1 largely overlap.
Figure 4: PDZ domain–mediated interaction between GRIP1 and Fras1.
Figure 5: GRIP1 is required for normal trafficking and biological activity of Fras1.

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Acknowledgements

We thank L. Sorokin, L. Bruckner-Tuderman, M.P. Marinkovich, R. Timpl and K. Hodivala-Dilke for antibodies and reagents and F. Watt and R. Klein for discussions and comments on the manuscript. This work was funded by Cancer Research UK, the EMBO Young Investigator Program (R.H.A.), the British Heart Foundation (P.J.S.), the Howard Hughes Medical Institute, the Robert Packard Center for ALS Research at Johns Hopkins and the US National Institute of Neurological Disorders and Stroke (R.L.H.).

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Authors and Affiliations

  1. Department of Neuroscience, Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Kogo Takamiya & Richard L Huganir

  2. Vascular Development Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK

    Vassiliki Kostourou, Susanne Adams & Ralf H Adams

  3. Molecular Medicine Unit, Institute of Child Health, London, WC1N 1EH, UK

    Shalini Jadeja & Peter J Scambler

  4. Department of Biology, University of Crete, Heraklion, 71409, Crete, Greece

    Georges Chalepakis

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  1. Kogo Takamiya
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Correspondence to Ralf H Adams.

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Takamiya, K., Kostourou, V., Adams, S. et al. A direct functional link between the multi-PDZ domain protein GRIP1 and the Fraser syndrome protein Fras1. Nat Genet 36, 172–177 (2004). https://doi.org/10.1038/ng1292

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