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Thyroid transcription factors in development, differentiation and disease

Key Points

  • Homeobox protein Nkx2.1 (NKX2-1), forkhead box protein E1 (FOXE1), paired box protein Pax8 (PAX8) and haematopoietically-expressed homeobox protein Hhex (HHEX) are transcriptional regulators of thyroid-specific genes

  • NKX-2-1 and HHEX are members of the homeodomain family, FOXE1 is a forkhead domain protein and PAX8 is a member of the paired domain family

  • Simultaneous expression of the four thyroid transcription factors (TTFs) occurs exclusively in differentiated thyroid follicular cells and their precursors, and this expression pattern is a unique hallmark of thyroid tissue

  • Alterations in expression of the TTFs that result from mutations, polymorphisms and/or epigenetic modifications can give rise to several pathologies including thyroid dysgenesis and thyroid cancer

Abstract

Identification of the thyroid transcription factors (TTFs), NKX2-1, FOXE1, PAX8 and HHEX, has considerably advanced our understanding of thyroid development, congenital thyroid disorders and thyroid cancer. The TTFs are fundamental to proper formation of the thyroid gland and for maintaining the functional differentiated state of the adult thyroid; however, they are not individually required for precursor cell commitment to a thyroid fate. Although knowledge of the mechanisms involved in thyroid development has increased, the full complement of genes involved in thyroid gland specification and the signals that trigger expression of the genes that encode the TTFs remain unknown. The mechanisms involved in thyroid organogenesis and differentiation have provided clues to identifying the genes that are involved in human congenital thyroid disorders and thyroid cancer. Mutations in the genes that encode the TTFs, as well as polymorphisms and epigenetic modifications, have been associated with thyroid pathologies. Here, we summarize the roles of the TTFs in thyroid development and the mechanisms by which they regulate expression of the genes involved in thyroid differentiation. We also address the implications of mutations in TTFs in thyroid diseases and in diseases not related to the thyroid gland.

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Figure 1: Expression of thyroid transcription factors and the stages of thyroid development.
Figure 2: TTFs in thyroid differentiation.
Figure 3: Consensus binding motifs of TTFs.
Figure 4: Novel TTF target genes.

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Acknowledgements

The authors' work was supported by Grants BFU-2010–16025 and SAF2013-44709R from the Dirección General de Proyectos de Investigación; RD12/0036/0030 from FIS, Instituto de Salud Carlos III; and S2011/BMD-2328 from the TIRONET project from the Comunidad de Madrid. A.L.-M. holds a predoctoral Formación Personal Investigador fellowship from the Universidad Autónoma de Madrid. L.P.F. holds a postdoctoral Junta de Ampliación de Estudios-Doctores fellowship from the Consejo Superior de Investigaciones Científicas. We are grateful to Dr Ronald Hartong for critical reading of the manuscript and for assistance with language editing.

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Fernández, L., López-Márquez, A. & Santisteban, P. Thyroid transcription factors in development, differentiation and disease. Nat Rev Endocrinol 11, 29–42 (2015). https://doi.org/10.1038/nrendo.2014.186

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