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Ewing sarcoma is the second most common skeletal (bone and cartilage) cancer in adolescents, and it is characterized by the expression of the aberrant chimeric fusion gene  EWS/FLI1.  Wild-type EWS has been proposed to play a role in mitosis, splicing and transcription. We have previously shown that EWS/FLI1 interacts with EWS, and it inhibits EWS activity in a dominant manner. Ewing sarcoma is a cancer that specifically develops in skeletal tissues, and although the above data suggests the significance of EWS, its role in chondrogenesis/skeletogenesis is not understood. To elucidate the function of EWS in skeletal development, we generated and analyzed a maternal zygotic (MZ)  ewsa/ewsa  line because the  ewsa/wt  and  ewsa/ewsa  zebrafish appeared to be normal and fertile. Compared with  wt/wt,  the Meckel’s cartilage of MZ  ewsa/ewsa  mutants had a higher number of craniofacial prehypertrophic chondrocytes that failed to mature into hypertrophic chondrocytes at 4 days post-fertilization (dpf). Ewsa interacted with Sox9, which is the master transcription factor for chondrogenesis. Sox9 target genes were either upregulated ( ctgfa, ctgfb, col2a1a,  and  col2a1b ) or downregulated ( sox5, nog1, nog2,  and  bmp4 ) in MZ  ewsa/ewsa  embryos compared with the wt/wt zebrafish embryos. Among these Sox9 target genes, the chromatin immunoprecipitation (ChIP) experiment demonstrated that Ewsa directly binds to  ctgfa  and  ctgfb  loci. Consistently, immunohistochemistry showed that the Ctgf protein is upregulated in the Meckel’s cartilage of MZ  ewsa/ewsa  mutants. Together, we propose that Ewsa promotes the differentiation from prehypertrophic chondrocytes to hypertrophic chondrocytes of Meckel’s cartilage through inhibiting Sox9 binding site of the  ctgf  gene promoter. Because Ewing sarcoma specifically develops in skeletal tissue that is originating from chondrocytes, this new role of EWS may provide a potential molecular basis of its pathogenesis.

Ewing Sarcoma Ewsa Protein Regulates Chondrogenesis of Meckel’s Cartilage through Modulation of Sox9 in Zebrafish