IDENTIFICATION OF A NOVEL BONE MORPHOGENETIC PROTEIN-RESPONSIVE GENE THAT MAY FUNCTION AS A NONCODING RNA

Bone morphogenetic proteins (BMPs)/osteogenic proteins (OPs), members of the transforming growth factor-beta superfamily, have a wide variet y of effects on many cell types including osteoblasts and chondroblast s, and play critical roles in embryonic development, BMPs transduce th eir effects through binding to two different types of serine/threonine kinase receptors, type I and type II. Signaling by these receptors is mediated by the recently identified Smad proteins. Despite the rapid progress in understanding of the signaling mechanism downstream of BMP receptors, the target genes of BMPs are poorly understood in mammals. Here we identified a novel gene, termed BMP/OP-responsive gene (BORG) , in C2C12 mouse myoblast cell line which trans-differentiates into os teoblastic cells in response to BMPs. Expression of BORG was dramatica lly induced in C2C12 cells by the treatment with BMP-2 or OP-l within 2 h and peaked at 12-24 h, whereas transforming growth factor-beta had a minimal effect. BMP-dependent expression of BORG was also detected in other cell types which are known to respond to BMPs, suggesting tha t BORG is a common target gene of BMPs. Cloning and sequence analysis of BORG; cDNA and the genomic clones revealed that, unexpectedly, the transcript of BORG lacks any extensive open reading frames and contain s a cluster of multiple interspersed repetitive sequences in its middl e part. The unusual structural features suggested that BORG may functi on as a noncoding RNA, although it is spliced and polyadenylated as au thentic protein-coding mRNAs. Together with the observation that trans fection of antisense oligonucleotides of BORG partially inhibited BMP- induced differentiation in C2C12 cells, it is possible that a new clas s of RNA molecules may have certain roles in the differentiation proce ss induced by BMPs.