ROLE OF THE TRANSCRIPTIONAL REGULATOR FHL2 IN BONE FORMATION: IDENTIFICATION OF FISH BONE-SPECIFIC TARGET GENES AND REGULATORY MECHANISMS

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Role of the transcriptional regulator FHL2: identification of fish target genes and regulatory mechanisms

Publication . Rafael, Marta S.; Cancela, Leonor; Laizé, Vincent; Schüle, R.

Four and a half LIM domains protein 2 (FHL2) is a multifunctional molecule, recognized for its involvement in central cellular regulatory mechanisms, including gene transcription, signal transduction and modulation of cytoskeleton architecture. Physiologically, FHL2 was shown to be associated with bone metabolism, skin wound healing response and muscle regeneration process. Despite many studies to unveil mechanisms of FHL2 action, all of them using mammalian models, available data are still insufficient to fully understand its physiological role, particularly during early development. This work presents original insights on FHL2 tissue patterning and mechanisms of action using the teleost gilthead seabream (S. aurata, L.) as a vertebrate model. First, we collected evidence that FHL2 transcript is strongly associated with development of fish craniofacial musculature and it is specific for red/slow muscle cells never described before. Then, and to better characterise the relevance of FHL2 on tissue mineralization, we engineered seabream VSa16 pre‐osteoblastic cell line to overexpress the corresponding protein. Surprisingly, extracellular matrix mineralization capacity was impaired and cells dedifferentiated through an epithelialmesenchymal transition‐like mechanism, known to be involved in progression of cells towards a cancer phenotype and their capacity of migration. This finding is extremely relevant since FHL2 has been repeatedly related with various cancer types. Finally, and although experimental data is still missing, we also present human transcriptional data towards a possible link between FHL2 gene expression and cancerous tissues. In addition, protein structure and phylogenetic studies indicate that FHL2 protein is remarkably conserved among vertebrate species. We propose that protein function has been conserved from fish to human and that fish is therefore a suitable vertebrate model to further study mechanisms of FHL2 action.

2011Doctoral thesis

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