Fishing the Molecular Bases of Treacher Collins Syndrome

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.

Beyond the Binding Site: In Vivo Identification of tbx2, smarca5 and wnt5b as Molecular Targets of CNBP during Embryonic Development

“…Indeed, our results showed that CNBP depletion leads to tbx2 down-regulation and, moreover, to p21 up-regulation trough a p53-independent pathway. On the other hand, cnbp was reported as a gene likely involved in Treacher Collins Syndrome (TCS, OMIM #154500) [33]. TCS is an autosomal dominant craniofacial malformation caused by mutations in the Treacher Collins-Franceschetti syndrome 1 gene (TCOF1, OMIM*606847).…”

“…TCS is an autosomal dominant craniofacial malformation caused by mutations in the Treacher Collins-Franceschetti syndrome 1 gene (TCOF1, OMIM*606847). In zebrafish, tcof1 loss-of-function represses tbx2 expression while up-regulates ndrg1 (N-myc downregulated gene 1) and p21 expressions [33]. Since Tbx2 represses the expression of ndrg1 acting as a co-repressor through recruitment of EGR1 [34], the role of CNBP as tbx2 up-regulator may explain not only the increase of p21 expression detected in cnbp-and tcof1-morphants but also the increase of ndrg1 expression detected in TCS-like zebrafish embryos.…”

“…CNBP regulatory genetic network. CNBP regulatory genetic relationships were obtained using Biotapestry software from data achieved in this work (*) as well as previous data from our group [33] and others [32,34] …”

Genetic Factors in Selected Complex Congenital Malformations with Cleft Defect

“…According to recent studies, the pathogenesis of TCS is also related to p53: mutation in one allele of the TCOF1 gene induces cellular stress that activates p53, which leads to death and abnormal differentiation of neuroepithelial cells [58]. An animal model of TCS with a TCOF1-equivalent gene has al- [59]. Further use of this model should demonstrate the exact role of TCOF1 in the formation of TCS.…”

Speech language pathology findings in a Treacher Collins syndrome patient

“…The first syndrome-related gene, TCOF1, was only identified in 1996 6 . Mutations in this gene are responsible for about 90% of TCS cases 7 . Over 130 pathogenic mutations have already been identified in TCOF1 gene 5 .…”