Abstract
Through forward genetic screening for mutations affecting visual system development, we identified prominent coloboma and cell-autonomous retinal neuron differentiation, lamination and retinal axon projection defects in eisspalte (ele) mutant zebrafish. Additional axonal deficits were present, most notably at midline axon commissures. Genetic mapping and cloning of the ele mutation showed that the affected gene is slbp, which encodes a conserved RNA stem-loop binding protein involved in replication dependent histone mRNA metabolism. Cells throughout the central nervous system remained in the cell cycle in ele mutant embryos at stages when, and locations where, post-mitotic cells have differentiated in wild-type siblings. Indeed, RNAseq analysis showed down-regulation of many genes associated with neuronal differentiation. This was coincident with changes in the levels and spatial localisation of expression of various genes implicated, for instance, in axon guidance, that likely underlie specific ele phenotypes. These results suggest that many of the cell and tissue specific phenotypes in ele mutant embryos are secondary to altered expression of modules of developmental regulatory genes that characterise, or promote transitions in, cell state and require the correct function of Slbp-dependent histone and chromatin regulatory genes.
Highlights
Mutations in a wide variety of genes are known to lead to congenital abnormalities of eye formation [1,2]
The eisspalte phenotype was originally identified on the basis of aberrant morphogenesis of the midbrain/hindbrain boundary [7] but the affected gene had not been identified. Using both traditional mapping approaches and a novel mapping-by-sequencing approach based on the variant discovery mapping Cloudmap pipeline [8,9], we find that the eisspalte mutation lies within the slbp gene
The ele mutant was originally identified in a screen for mutations affecting brain morphology with the phenotype described as a dent in the midbrain-hindbrain boundary (MHB) [7]
Summary
Mutations in a wide variety of genes are known to lead to congenital abnormalities of eye formation [1,2] Some of these genes, such as pax and rx, show temporally and spatially restricted expression within developing visual system structures and a priori, are obvious candidates for roles in eye formation [3]. The eisspalte phenotype was originally identified on the basis of aberrant morphogenesis of the midbrain/hindbrain boundary [7] but the affected gene had not been identified Using both traditional mapping approaches and a novel mapping-by-sequencing approach based on the variant discovery mapping Cloudmap pipeline [8,9], we find that the eisspalte mutation lies within the slbp gene. This is consistent with a description of retinal defects in another slbprw440 mutant allele [10]
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