Genetic Analysis of Fin Development in Zebrafish Identifies Furin and hemicentin1 as Potential Novel Fraser Syndrome Disease Genes

PLoS Genet. 2010 Apr 15;6(4):e1000907. doi: 10.1371/journal.pgen.1000907.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Embryo, Nonmammalian / metabolism*
  • Extracellular Matrix Proteins / genetics*
  • Extracellular Matrix Proteins / metabolism
  • Frasier Syndrome / genetics*
  • Furin / genetics*
  • Furin / metabolism
  • Gene Expression Regulation, Developmental
  • Mice
  • Molecular Sequence Data
  • Mutation*
  • Proprotein Convertases / genetics*
  • Proprotein Convertases / metabolism
  • Zebrafish / embryology*
  • Zebrafish Proteins / genetics*
  • Zebrafish Proteins / metabolism

Substances

  • Extracellular Matrix Proteins
  • Frem1 protein, mouse
  • Hmcn1 protein, zebrafish
  • Zebrafish Proteins
  • FurinA protein, zebrafish
  • Proprotein Convertases
  • Furin