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Fras1 deficiency results in cryptophthalmos, renal agenesis and blebbed phenotype in mice
Sophia Vrontou1, Petros Petrou, Barbara I Meyer
1Institute of Molecular Biology and Biotechnology, FO.R.T.H., Heraklion 71110, Crete, Greece.
Abstract:
Loss of tight association between epidermis and dermis underlies several blistering disorders and is frequently caused by impaired function of extracellular matrix (ECM) proteins. 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 mutants, which have been considered a model for the human genetic disorder Fraser syndrome. We show that bl/bl homozygous embryos are devoid of Fras1 protein, consistent with the finding that Fras1 is mutated in these mice. 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.
Insights
Researchers identified Fras1, an extracellular matrix protein crucial for skin and kidney development. Its absence causes blistering disorders and kidney defects, linking it to Fraser syndrome.
Area of Science:
- Developmental Biology
- Genetics
- Dermatology
Background:
- Blistering disorders often stem from impaired extracellular matrix (ECM) protein function.
- The precise molecular mechanisms underlying these disorders require further elucidation.
Purpose of the Study:
- To identify and characterize novel proteins involved in epidermal-dermal adhesion.
- To investigate the function of the newly identified protein, Fras1, in embryonic development.
Main Methods:
- Analysis of gene expression patterns in mouse embryos.
- Phenotypic characterization of genetically modified mice lacking Fras1 function.
- Comparison of Fras1-deficient mice with existing models of blistering disorders.
Main Results:
- A novel protein, Fras1, was identified underlying the epidermis and other epithelia.
- Loss of Fras1 function led to subepidermal blisters and renal agenesis in mouse embryos.
- Fras1 deficiency phenocopied the 'blebbed' mouse mutant, a model for human Fraser syndrome.
Conclusions:
- Fras1 is essential for maintaining epithelial integrity and normal kidney development.
- Mutations in Fras1 are implicated in the pathogenesis of Fraser syndrome.
- Disruptions in the extracellular matrix beneath epithelia can cause blistering and developmental abnormalities.
