TITLE

Genetic defects of GDF6 in the zebrafish out of sight mutant and in human eye developmental anomalies

AUTHOR(S)
den Hollander, Anneke I.; Biyanwila, Janisha; Kovach, Peter; Bardakjian, Tanya; Traboulsi, Elias I.; Ragge, Nicola K; Schneider, Adele; Malicki, Jarema
PUB. DATE
January 2010
SOURCE
BMC Genetics;2010, Vol. 11, p102
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Background: The size of the vertebrate eye and the retina is likely to be controlled at several stages of embryogenesis by mechanisms that affect cell cycle length as well as cell survival. A mutation in the zebrafish out of sight (out) locus results in a particularly severe reduction of eye size. The goal of this study is to characterize the outm233 mutant, and to determine whether mutations in the out gene cause microphthalmia in humans. Results: In this study, we show that the severe reduction of eye size in the outm233 mutant is caused by a mutation in the zebrafish gdf6a gene. Despite the small eye size, the overall retinal architecture appears largely intact, and immunohistochemical studies confirm that all major cell types are present in outm233 retinae. Subtle cell fate and patterning changes are present predominantly in amacrine interneurons. Acridine orange and TUNEL staining reveal that the levels of apoptosis are abnormally high in outm233 mutant eyes during early neurogenesis. Mutation analysis of the GDF6 gene in 200 patients with microphthalmia revealed amino acid substitutions in four of them. In two patients additional skeletal defects were observed. Conclusions: This study confirms the essential role of GDF6 in the regulation of vertebrate eye size. The reduced eye size in the zebrafish outm233 mutant is likely to be caused by a transient wave of apoptosis at the onset of neurogenesis. Amino acid substitutions in GDF6 were detected in 4 (2%) of 200 patients with microphthalmia. In two patients different skeletal defects were also observed, suggesting pleitrophic effects of GDF6 variants. Parents carrying these variants are asymptomatic, suggesting that GDF6 sequence alterations are likely to contribute to the phenotype, but are not the sole cause of the disease. Variable expressivity and penetrance suggest a complex non- Mendelian inheritance pattern where other genetic factors may influence the outcome of the phenotype.
ACCESSION #
55534026

 

Related Articles

  • Proteomics of early zebrafish embryos. Link, Vinzenz; Shevchenko, Andrej; Heisenberg, Carl-Philipp // BMC Developmental Biology;2006, Vol. 6, p1 

    Background: Zebrafish (D. rerio) has become a powerful and widely used model system for the analysis of vertebrate embryogenesis and organ development. While genetic methods are readily available in zebrafish, protocols for two dimensional (2D) gel electrophoresis and proteomics have yet to be...

  • Embryonic Senescence and Laminopathies in a Progeroid Zebrafish Model. Koshimizu, Eriko; Imamura, Shintaro; Qi, Jie; Toure, Jamal; Jr., Delgado M. Valdez; Carr, Christopher E.; Hanai, Jun-ichi; Kishi, Shuji // PLoS ONE;2011, Vol. 6 Issue 3, p1 

    Background: Mutations that disrupt the conversion of prelamin A to mature lamin A cause the rare genetic disorder Hutchinson-Gilford progeria syndrome and a group of laminopathies. Our understanding of how A-type lamins function in vivo during early vertebrate development through aging remains...

  • Identification of Estrogen Target Genes during Zebrafish Embryonic Development through Transcriptomic Analysis. Hao, Ruixin; Bondesson, Maria; Singh, Amar V.; Riu, Anne; McCollum, Catherine W.; Knudsen, Thomas B.; Gorelick, Daniel A.; Gustafsson, Jan-Åke // PLoS ONE;Nov2013, Vol. 8 Issue 11, p1 

    Estrogen signaling is important for vertebrate embryonic development. Here we have used zebrafish (Danio rerio) as a vertebrate model to analyze estrogen signaling during development. Zebrafish embryos were exposed to 1 µM 17β-estradiol (E2) or vehicle from 3 hours to 4 days post...

  • Timeline: Headwaters of the zebrafish ? emergence of a new model vertebrate. Grunwald, David Jonah; Eisen, Judith S. // Nature Reviews Genetics;Sep2002, Vol. 3 Issue 9, p717 

    The understanding of vertebrate development has advanced considerably in recent years, primarily due to the study of a few model organisms. The zebrafish, the newest of these models, has risen to prominence because both genetic and experimental embryological methods can be easily applied to this...

  • Global changes in genomic methylation levels during early development of the zebrafish embryo. Mhanni, A. A.; McGowan, R. A. // Development Genes & Evolution;Aug2004, Vol. 214 Issue 8, p412 

    We have examined the methylation status of the zebrafish genome during early embryogenesis and we find evidence that methylation fluxes do occur in that organism. The parental genetic contributions to the zygote are, initially, differently methylated with the genome of the sperm being...

  • Genomewide Expression Profiling in the Zebrafish Embryo Identifies Target Genes Regulated by Hedgehog Signaling During Vertebrate Development. Jun Xu; Srinivas, Bhylahalli P.; Shang Yew Tay; Mak, Alicia; Xianwen Yu; Lee, Serene G. P.; Henry Yang; Govindarajan, Kunde R.; Leong, Bernard; Bourque, Guillaume; Mathavant, Sinnakarupan; Roy, Sudlipto // Genetics;Oct2006, Vol. 174 Issue 2, p735 

    Hedgehog proteins play critical roles in organizing the embryonic development of animals, largely through modulation of target gene expression. Little is currently known, however, about the kinds and numbers of genes whose expression is controlled, directly or indirectly, by Hedgehog activity....

  • Zebrafish transgenic Enhancer TRAP line database (ZETRAP). Choo, Benjamin G.H.; Kondrichin, Igor; Parinov, Sergey; Emelyanov, Alexander; Go, William; Wei-chang Toh; Korzh, Vladimir // BMC Developmental Biology;2006, Vol. 6, p5 

    Background: The zebrafish, Danio rerio, is used as a model organism to study vertebrate genetics and development. An effective enhancer trap (ET) in zebrafish using the Tol2 transposon has been demonstrated. This approach could be used to study embryogenesis of a vertebrate species in real time...

  • A zebrafish screen for craniofacial mutants identifies wdr68 as a highly conserved gene required for endothelin-1 expression. Nissen, Robert M.; Amsterdam, Adam; Hopkins, Nancy // BMC Developmental Biology;2006, Vol. 6, p1 

    Background: Craniofacial birth defects result from defects in cranial neural crest (NC) patterning and morphogenesis. The vertebrate craniofacial skeleton is derived from cranial NC cells and the patterning of these cells occurs within the pharyngeal arches. Substantial efforts have led to the...

  • Isolation and Genetic Characterization of Mother-of-Snow-White, a Maternal Effect Allele Affecting Laterality and Lateralized Behaviors in Zebrafish. Domenichini, Alice; Dadda, Marco; Facchin, Lucilla; Bisazza, Angelo; Argenton, Francesco // PLoS ONE;2011, Vol. 6 Issue 10, p1 

    In the present work we report evidence compatible with a maternal effect allele affecting left-right development and functional lateralization in vertebrates. Our study demonstrates that the increased frequency of reversed brain asymmetries in a zebrafish line isolated through a behavioral assay...

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics