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Fras1 deficiency results in cryptophthalmos, renal agenesis and blebbed phenotype in mice

Abstract

Loss of tight association between epidermis and dermis underlies several blistering disorders and is frequently caused by impaired function of extracellular matrix (ECM) proteins1,2. Here we describe a new protein in mouse, Fras1, that is specifically detected in a linear fashion underlying the epidermis and the basal surface of other epithelia in embryos. Loss of Fras1 function results in the formation of subepidermal hemorrhagic blisters as well as unilateral or bilateral renal agenesis during mouse embryogenesis. Postnatally, homozygous Fras1 mutants have fusion of the eyelids and digits and unilateral renal agenesis or dysplasia. The defects observed in Fras1−/− mice phenocopy those of the existing bl (blebbed) mouse mutants3,4, which have been considered a model for the human genetic disorder Fraser syndrome5,6. We show that bl/bl homozygous embryos are devoid of Fras1 protein, consistent with the finding that Fras1 is mutated in these mice6. In sum, our data suggest that perturbations in the composition of the extracellular space underlying epithelia could account for the onset of the blebbed phenotype in mouse and Fraser syndrome manifestation in human.

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Figure 1: Schematic representation of Fras1 and detection of the mRNA and protein.
Figure 2: Targeted disruption of Fras1.
Figure 3: Onset and progression of blister formation in Fras1−/− embryos on the C57BL/10 background.
Figure 4: Fras1−/− mice on the NMRI background have fusions of eyelids and digits as well as renal agenesis or dysgenesis.
Figure 5: Comparative analysis of the DEJ zone of wild-type, Fras1−/− and bl/bl embryos.
Figure 6: Analysis of the DEJ zone of blistered skin in Fras1−/− embryos.

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Acknowledgements

We thank S. Meyer and S. Mahsur for help with the mouse stem cells and morula aggregation; E. Pavlakis for technical assistance; R. Timpl for the antibodies for laminin α5, laminin γ1, agrin and nidogen 1; P. Bonaldo for the collagen VI antibody; L. Bruckner-Tuderman for collagen VII antibodies; H. Krambovitis for the generation of Fras1 antibodies; L. Panagis, C. Dermon and G. Mavrothalassitits for help with the TUNEL assay; A. Argyrokastritis and S. Theophilou for critical reading of the manuscript; and P. Gruss for providing expertise and facilities of his laboratory. This work was supported by a grant from the Greek General Secretariat for Science and Technology and the British Heart Foundation (to P.J.S.).

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Correspondence to Georges Chalepakis.

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Vrontou, S., Petrou, P., Meyer, B. et al. Fras1 deficiency results in cryptophthalmos, renal agenesis and blebbed phenotype in mice. Nat Genet 34, 209–214 (2003). https://doi.org/10.1038/ng1168

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