Identification and developmental expression of the zebrafish orthologue of the tumor suppressor gene HIC1

Hypermethylated in Cancer 1 (HIC1) is a human tumor suppressor gene located at chromosome 17p13.3 which is frequently hypermethylated and transcriptionally silent in many types of tumors. In addition, its location in the Miller-Dieker syndrome's (MDS) deletion region, its embryonic expression pattern in mice and the phenotype of the HIC1-deficient mice have provided strong evidence for its implication in this contiguous-gene syndrome. HIC1 encodes a five C2H2-type zinc finger transcriptional repressor belonging to the BTB/POZ family. We have isolated the true zebrafish orthologue of human HIC1 since it has a comparable intron-exon structure and since its predicted gene product, ZfHIC1 displays much higher sequence similarities in its overall sequence (737 residues) with human HIC1 (714 residues) than the 454 residues encoded by the only zebrafish HIC1 sequence (AF111712) described so far, which has been renamed ZfHIC1alpha. Notably, the C-terminal end and one zinc finger in the DNA-binding domain are missing in ZfHIC1alpha. As a consequence, ZfHIC1 proteins bind the human HIC1 consensus DNA-binding sequence in vitro, whereas ZfHIC1alpha cannot. Analyses of the expression pattern of ZfHIC1 and of its paralogue ZfHRG22 (HIC1 related gene on chromosome 22) show that they share expression domains with their respective orthologous vertebrate genes. ZfHRG22 is prominently expressed in the brain and in neural tissues. Interestingly, the predominant expression of ZfHIC1 in the mesenchyme of the head, around the nose and the eye and in the branchial arches is possibly consistent with some of the abnormalities seen in the HIC1-deficient mice and provides another clue for the implication of HIC1 in MDS.