The mechanisms underlying Treacher Collins syndrome phenotype involve CNBP deficiency

WEINER, ANDREA ; MOUGUELAR, VALERIA S.; COUX, GABRIELA; CALCATERRA, NORA B

Rosario

Congreso; Second Meeting of LAZEN; 2012

Latin American Zebrafish Network

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 limited, probably due to the difficulty of reproducing the pathology in experimental animals. Previously, we informed that it is possible to achieve fish with TCS-like phenotype by knocking down the expression of the tcof1 ortholog in zebrafish and, using this model, we identified a set of genes as putative candidates for explaining TCS symptoms. Among the genes displaying differential expression, we detected a significant reduction of cnbp mRNA levels in TCS-like fish. Our goal in this work was to assess CNBP role in tcof morphants. A careful examination of CNBP knock-down and TCOF knock-down fish phenotypes revealed numerous similarities: round head instead of triangular, fronto-nasal hipoplasia, abnormal brain, increased apoptosis in eye and brain, and aberrant craniofacial cartilage development (analysed by Alcian Blue staining). To better explore the role of CNBP in TCS-fish, we microinjected embryos with the tcof morpholino oligonucleotide plus cnbp mRNA. The abnormal phenotype was totally (74.6%) or partially (25.4%) reverted in these fish. Altogether, our results show that it was possible to rescue fish with TCS-like phenotype by over expressing CNBP in TCOF-knocked-down zebrafish. This data suggest the existence of a new pathway during embryonic development involving TCOF and CNBP that controls cell proliferation and apoptosis.