title: Basement membrane assembly of the integrin α8β1 ligand nephronectin requires Fraser syndrome-associated proteins.
abstract: Dysfunction of the basement membrane protein QBRICK provokes Fraser syndrome, which results in renal dysmorphogenesis, cryptophthalmos, syndactyly, and dystrophic epidermolysis bullosa through unknown mechanisms. Here, we show that integrin α8β1 binding to basement membranes was significantly impaired in Qbrick-null mice. This impaired integrin α8β1 binding was not a direct consequence of the loss of QBRICK, which itself is a ligand of integrin α8β1, because knock-in mice with a mutation in the integrin-binding site of QBRICK developed normally and do not exhibit any defects in integrin α8β1 binding. Instead, the loss of QBRICK significantly diminished the expression of nephronectin, an integrin α8β1 ligand necessary for renal development. In vivo, nephronectin associated with QBRICK and localized at the sublamina densa region, where QBRICK was also located. Collectively, these findings indicate that QBRICK facilitates the integrin α8β1-dependent interactions of cells with basement membranes by regulating the basement membrane assembly of nephronectin and explain why renal defects occur in Fraser syndrome.
authors.affiliation: Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Daiji
authors.initials: D
authors.lastname: Kiyozumi
authors.forename: Makiko
authors.initials: M
authors.lastname: Takeichi
authors.forename: Itsuko
authors.initials: I
authors.lastname: Nakano
authors.forename: Yuya
authors.initials: Y
authors.lastname: Sato
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Fukuda
authors.forename: Kiyotoshi
authors.initials: K
authors.lastname: Sekiguchi
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000172:deficiency / Q000378:metabolism*; D005260:Female; D058497:Fraser Syndrome; D016023:Integrins / Q000378:metabolism*; D008024:Ligands; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout
chemical_list: D016326:Extracellular Matrix Proteins; C482018:Fras1 protein, mouse; C492585:Frem1 protein, mouse; C504802:Frem2 protein, mouse; D016023:Integrins; D008024:Ligands; C094866:integrin alpha8beta1; C432915:nephronectin