A zebrafish ribosomopathy links Ddx49-dependent ribosome biogenesis to differential failure of population expansion among pigment cell lineages

Abstract

Defects in ribosome biogenesis cause surprisingly cell-type specific pathologies. Why some cells are more vulnerable than others remains unresolved. Here, we show that a zebrafish pigment pattern mutant, sisley, results from a viable missense allele of ddx49, encoding a DEAD-box RNA helicase required for small ribosomal subunit biogenesis and early survival. In mutants, yellow/orange xanthophores fail to proliferate during development of the adult stripe pattern, whereas closely related melanophores are affected only mildly. The mutant protein has reduced helicase but increased ATPase activity and, consistent with impaired ribosome biogenesis in vivo, mutants are deficient in 18S rRNA relative to its precursor. Remarkably, a similar deficiency in 18S rRNA relative to precursor rRNA distinguishes xanthophores from melanophores even in the wild-type, suggesting an inherent difference in rRNA processing that leaves xanthophores vulnerable to Ddx49 dysfunction. Both xanthophore deficiency and a male-biased sex ratio of the sisley mutant were rescued by mutation of tp53. Our findings suggest how baseline differences in ribosome production shape cell-type specific outcomes of mutations affecting ribosome biogenesis, and provide an adult-viable model for Ddx49 function in vivo.