title: Mutations in laminin alpha 1 result in complex, lens-independent ocular phenotypes in zebrafish.
abstract: We report phenotypic and genetic analyses of a recessive, larval lethal zebrafish mutant, bal(a69), characterized by severe eye defects and shortened body axis. The bal(a69) mutation was mapped to chromosome 24 near the laminin alpha 1 (lama1) gene. We analyzed the lama1 gene sequence within bal(a69) embryos and two allelic mutants, bal(arl) and bal(uw1). Missense (bal(a69)), nonsense (bal(arl)), and frameshift (bal(uw1)) alterations in lama1 were found to underlie the phenotypes. Extended analysis of bal(a69) ocular features revealed disrupted lens development with subsequent lens degeneration, focal cornea dysplasia, and hyaloid vasculature defects. Within the neural retina, the ganglion cells showed axonal projection defects and ectopic photoreceptor cells were noted at inner retinal locations. To address whether ocular anomalies were secondary to defects in lens differentiation, bal(a69) mutants were compared to embryos in which the lens vesicle was surgically removed. Our analysis suggests that many of the anterior and posterior ocular defects in bal(a69) are independent of the lens degeneration. Analysis of components of focal adhesion signaling complexes suggests that reduced focal adhesion kinase activation underlies the anterior segment dysgenesis in lama1 mutants. To assess adult ocular phenotypes associated with lama1 mutations, genetic mosaics were generated by transplanting labeled bal cells into ocular-fated regions of wild-type blastulas. Adult chimeric eyes displayed a range of defects including anterior segment dysgenesis and cataracts. Our analysis provides mechanistic insights into the developmental defects and ocular pathogenesis caused by mutations in laminin subunits.
authors.affiliation: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Semina
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Bosenko
authors.forename: Natalya C
authors.initials: NC
authors.lastname: Zinkevich
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Soules
authors.forename: David R
authors.initials: DR
authors.lastname: Hyde
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Vihtelic
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Willer
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Gregg
authors.forename: Brian A
authors.initials: BA
authors.lastname: Link
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000869:Anterior Eye Segment / Q000002:abnormalities / Q000166:cytology / Q000196:embryology; D001483:Base Sequence; D002386:Cataract / Q000473:pathology; D002875:Chromosomes / Q000235:genetics; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000196:embryology; D022001:Focal Adhesions; D018507:Gene Expression Regulation, Developmental; D007797:Laminin / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics*; D007908:Lens, Crystalline / Q000002:abnormalities / Q000166:cytology / Q000196:embryology* / Q000601:surgery; D008969:Molecular Sequence Data; D009030:Mosaicism; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000166:cytology; D012171:Retinal Vessels / Q000002:abnormalities / Q000196:embryology; D015027:Zebrafish / Q000002:abnormalities / Q000196:embryology*
chemical_list: D007797:Laminin; D012333:RNA, Messenger; C084098:laminin A