Abstract
Using forward genetics, we have identified the genes mutated in two classes of zebrafish fin mutants. The mutants of the first class are characterized by defects in embryonic fin morphogenesis, which are due to mutations in a Laminin subunit or an Integrin alpha receptor, respectively. The mutants of the second class display characteristic blistering underneath the basement membrane of the fin epidermis. Three of them are due to mutations in zebrafish orthologues of FRAS1, FREM1, or FREM2, large basement membrane protein encoding genes that are mutated in mouse bleb mutants and in human patients suffering from Fraser Syndrome, a rare congenital condition characterized by syndactyly and cryptophthalmos. Fin blistering in a fourth group of zebrafish mutants is caused by mutations in Hemicentin1 (Hmcn1), another large extracellular matrix protein the function of which in vertebrates was hitherto unknown. Our mutant and dose-dependent interaction data suggest a potential involvement of Hmcn1 in Fraser complex-dependent basement membrane anchorage. Furthermore, we present biochemical and genetic data suggesting a role for the proprotein convertase FurinA in zebrafish fin development and cell surface shedding of Fras1 and Frem2, thereby allowing proper localization of the proteins within the basement membrane of forming fins. Finally, we identify the extracellular matrix protein Fibrillin2 as an indispensable interaction partner of Hmcn1. Thus we have defined a series of zebrafish mutants modelling Fraser Syndrome and have identified several implicated novel genes that might help to further elucidate the mechanisms of basement membrane anchorage and of the disease's aetiology. In addition, the novel genes might prove helpful to unravel the molecular nature of thus far unresolved cases of the human disease.
Highlights
Fraser Syndrome (FS) is a recessive polygenic, multisystem congenital human disorder characterised largely by syndactyly of the soft tissue of the digits, cryptophthalmos and renal agenesis, a myriad of other variable epithelial malformations have been reported, underscoring the complex and pleiotropic nature of the syndrome [1]
We demonstrate that the zebrafish is a useful model for elucidating mechanisms and novel players involved in Fraser Syndrome, and that the Fraser complex is an ancient invention with essential roles during the formation and/or function of basement membranes in particular epithelial structures of the developing embryo
To elucidate the mechanisms required for generating fins, we analysed zebrafish fin mutants isolated in previous [13] or more recent ENU mutagenesis screens conducted in the Hammerschmidt laboratory
Summary
Fraser Syndrome (FS) is a recessive polygenic, multisystem congenital human disorder characterised largely by syndactyly of the soft tissue of the digits, cryptophthalmos (fusion of the eye lids) and renal agenesis, a myriad of other variable epithelial malformations have been reported, underscoring the complex and pleiotropic nature of the syndrome [1]. Autozygosity mapping and candidate sequencing revealed that many Fraser syndrome cases are due to mutations in the genes encoding the proteins FRAS1 or FREM2, which belong to a family of large extracellular matrix proteins [2,3,4]. This protein family contains two further members, FREM1 and FREM3, these have not, so far, been implicated in Fraser Syndrome aetiology [5,6].
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