BioProject

The zebrafish has proven to be a versatile and valuable model for investigating the molecular and cellular basis of Fragile X syndrome (FXS). More...

The zebrafish has proven to be a versatile and valuable model for investigating the molecular and cellular basis of Fragile X syndrome (FXS). Reduction of expression of the zebrafish FMR1-ortholgous gene, fmr1, causes developmental and behavioural phenotypes related to the human syndrome. The hu2787 nonsense mutation allele of fmr1 is now the most widely used zebrafish model of FXS, although the FXS-relevant phenotypes seen from morpholino antisense oligonucleotide (morpholino) suppression of fmr1 transcript translation were not observed when this allele was first described. The subsequent discovery of genetic compensation, whereby morpholino-directed knockdown can give a more “pure” loss-of-function phenotype while mutations causing nonsense mediated decay of transcripts cause compensatory upregulation of homologous transcripts, suggested an explanation for the differences observed. To test for molecular evidence of genetic compensation in fmr1hu2787 homozygous mutants, we compared the transcriptomes of homozygous mutant and wild type larvae at 2 days post fertilisation. We observed statistically significant changes in the expression of a number of gene transcripts, but none with sequence homology to fmr1. Curiously, the majority of differentially expressed genes are located, like fmr1, on chromosome 14. Quantitative PCR tests on genomic DNA did not support that the apparent expression differences were artefacts due to changes in relative chromosome abundance. The coordinate dysregulation of chromosome 14 genes due to mutation of fmr1 supports this gene’s involvement in a chromosome-wide gene regulation complex. Overall design: Four clutches of zebrafish embryos were obtained from pair-matings of zebrafish homozygous for the hu2787 allele of fmr1. Another four clutches of zebrafish embryos were obtained from wild-type zebrafish. Each clutch was derived from a different pair of parents. Less...