Abstract
Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development, and mutations in the TCOF1 gene are responsible for over 90% of TCS cases. The knowledge about the molecular mechanisms responsible for this syndrome is relatively scant, probably due to the difficulty of reproducing the pathology in experimental animals. Zebrafish is an emerging model for human disease studies, and we therefore assessed it as a model for studying TCS. We identified in silico the putative zebrafish TCOF1 ortholog and cloned the corresponding cDNA. The derived polypeptide shares the main structural domains found in mammals and amphibians. Tcof1 expression is restricted to the anterior-most regions of zebrafish developing embryos, similar to what happens in mouse embryos. Tcof1 loss-of-function resulted in fish showing phenotypes similar to those observed in TCS patients, and enabled a further characterization of the mechanisms underlying craniofacial malformation. Besides, we initiated the identification of potential molecular targets of treacle in zebrafish. We found that Tcof1 loss-of-function led to a decrease in the expression of cellular proliferation and craniofacial development. Together, results presented here strongly suggest that it is possible to achieve fish with TCS-like phenotype by knocking down the expression of the TCOF1 ortholog in zebrafish. This experimental condition may facilitate the study of the disease etiology during embryonic development.
Highlights
Treacher Collins syndrome, known as mandibulofacial dysostosis (TCS, OMIM #154500), is an autosomal dominant craniofacial malformation affecting 1:10,000 newborns
We report here the identification of the formerly called B8JIY2 sequence as the TCOF1 ortholog in Danio rerio
Several factors strongly support our hypothesis that the cloned cDNA corresponds to the TCOF1 ortholog in zebrafish, including the LisH domain in the Nterminus; the histone H5 motifs in the C-terminus; its dynamic and anterior-most spatiotemporal expression pattern during embryonic development; its requirement for normal neural crest (NC) and craniofacial cartilage development; and its action on previously informed putative treacle targets
Summary
Treacher Collins syndrome, known as mandibulofacial dysostosis (TCS, OMIM #154500), is an autosomal dominant craniofacial malformation affecting 1:10,000 newborns. Mutations in the Treacher Collins-Franceschetti syndrome 1 gene (TCOF1, OMIM *606847), mapped to chromosome 5q32-q33.1, are responsible for over 90% of TCS cases. Over 120 pathogenic mutations have been identified in TCOF1. This observation suggests that haploinsufficiency of TCOF1’s protein product, treacle, is the underlying cause of TCS [3]. The majority of mutations in TCOF1 result in truncated treacle proteins [4,5,6,7,8,9], highlighting the importance of the C-terminal domain for treacle function. Treacle appears to participate in ribosome biogenesis by controlling pre-rRNA synthesis or processing [10,11,12]; the treacle biological role has not been fully understood yet
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