Identificazione di co-attivatori trascrizionali e di geni bersaglio per i fattori di trascrizione tessuto-specifici Pax 8 e TTF-1

The identity of each cell type is controlled mostly at the transcriptional level by unique combinations of transcription factors. The study of transcription factors regulating specific expression in differentiated cell culture systems allows the comprehension of the molecular mechanisms leading to cell differentiation and organogenesis. The transcription factors TTF-1 and Pax 8 play a pivotal role in thyroid follicular cells differentiation as well as thyroid differentiation marker genes transcriptional regulation. TTF-1 and Pax 8 cooperatively activate the expression of the thyroperoxidase (TPO) and thyroglobulin (Tg) genes involved in the synthesis of the thyroid hormones. Recently it has been shown that TTF-1 plays an important role in neuroendocrine cells of the hypothalamus, where it induces expression of the peptide luteinizing hormone-releasing hormone (LHRH) that regulates female sexual development in mammals. In this study we investigated two novel characteristics of these transcription factors: We showed that the retinoblastoma tumor suppressor protein (pRb) is in the complex assembled on the TPO gene promoter acting as a transcriptional coactivator of Pax 8. This finding identifies one of the molecular mechanisms underlying the relevant role of pRb in thyrocytes differentiation. II. We identified a set of genes activated by TTF-1 in immortalized hypothalamic LHRH neurons, by using microarrays. Among the genes identified, we confirmed that TTF-1 associates in vivo with the Sparc gene promoter. approach we used allows the systematic identification of functionally related genes downstream of TTF-1 important for the regulation of puberty.