Thyroid Transcription Factors in Development, Differentiation and Disease

Overview

Journal Nat Rev Endocrinol

Specialty Endocrinology

Date 2014 Oct 29

PMID 25350068

Citations 110

Authors

Lara P Fernandez

Aristides Lopez-Marquez

Pilar Santisteban

Affiliations

Soon will be listed here.

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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References

Civitareale D, Castelli M, Falasca P, Saiardi A . Thyroid transcription factor 1 activates the promoter of the thyrotropin receptor gene. Mol Endocrinol. 1993; 7(12):1589-95. DOI: 10.1210/mend.7.12.8145764. View

Nettore I, Mirra P, Ferrara A, Sibilio A, Pagliara V, Suemi Kamoi Kay C . Identification and functional characterization of a novel mutation in the NKX2-1 gene: comparison with the data in the literature. Thyroid. 2013; 23(6):675-82. DOI: 10.1089/thy.2012.0267. View

Macchia P . Recent advances in understanding the molecular basis of primary congenital hypothyroidism. Mol Med Today. 2000; 6(1):36-42. DOI: 10.1016/s1357-4310(99)01620-2. View

Butt S, Sousa V, Fuccillo M, Hjerling-Leffler J, Miyoshi G, Kimura S . The requirement of Nkx2-1 in the temporal specification of cortical interneuron subtypes. Neuron. 2008; 59(5):722-32. PMC: 2562525. DOI: 10.1016/j.neuron.2008.07.031. View

Dehbi M, Pelletier J . PAX8-mediated activation of the wt1 tumor suppressor gene. EMBO J. 1996; 15(16):4297-306. PMC: 452155. View

Sequeira M, Morgan J, Fuhrer D, Wheeler M, Jasani B, Ludgate M . Thyroid transcription factor-2 gene expression in benign and malignant thyroid lesions. Thyroid. 2002; 11(11):995-1001. DOI: 10.1089/105072501753271662. View

Crompton M, Bartlett T, Macgregor A, Manfioletti G, Buratti E, Giancotti V . Identification of a novel vertebrate homeobox gene expressed in haematopoietic cells. Nucleic Acids Res. 1992; 20(21):5661-7. PMC: 334400. DOI: 10.1093/nar/20.21.5661. View

Bopp D, Burri M, Baumgartner S, Frigerio G, Noll M . Conservation of a large protein domain in the segmentation gene paired and in functionally related genes of Drosophila. Cell. 1986; 47(6):1033-40. DOI: 10.1016/0092-8674(86)90818-4. View

Ngan E, Lang B, Liu T, Shum C, So M, Lau D . A germline mutation (A339V) in thyroid transcription factor-1 (TITF-1/NKX2.1) in patients with multinodular goiter and papillary thyroid carcinoma. J Natl Cancer Inst. 2009; 101(3):162-75. DOI: 10.1093/jnci/djn471. View

10.

Takahashi M, Saenko V, Rogounovitch T, Kawaguchi T, Drozd V, Takigawa-Imamura H . The FOXE1 locus is a major genetic determinant for radiation-related thyroid carcinoma in Chernobyl. Hum Mol Genet. 2010; 19(12):2516-23. DOI: 10.1093/hmg/ddq123. View

11.

Zhang P, Zuo H, Nakamura Y, Nakamura M, Wakasa T, Kakudo K . Immunohistochemical analysis of thyroid-specific transcription factors in thyroid tumors. Pathol Int. 2006; 56(5):240-5. DOI: 10.1111/j.1440-1827.2006.01959.x. View

12.

Fagman H, Andersson L, Nilsson M . The developing mouse thyroid: embryonic vessel contacts and parenchymal growth pattern during specification, budding, migration, and lobulation. Dev Dyn. 2005; 235(2):444-55. DOI: 10.1002/dvdy.20653. View

13.

Fagman H, Nilsson M . Morphogenetics of early thyroid development. J Mol Endocrinol. 2011; 46(1):R33-42. DOI: 10.1677/jme-10-0084. View

14.

Christophe-Hobertus C, Lefort A, Libert F, Christophe D . Functional inactivation of thyroid transcription factor-1 in PCCl3 thyroid cells. Mol Cell Endocrinol. 2012; 358(1):36-45. DOI: 10.1016/j.mce.2012.02.013. View

15.

Zannini M, Avantaggiato V, Biffali E, Arnone M, Sato K, Pischetola M . TTF-2, a new forkhead protein, shows a temporal expression in the developing thyroid which is consistent with a role in controlling the onset of differentiation. EMBO J. 1997; 16(11):3185-97. PMC: 1169936. DOI: 10.1093/emboj/16.11.3185. View

16.

Runkle E, Rice S, Qi J, Masser D, Antonetti D, Winslow M . Occludin is a direct target of thyroid transcription factor-1 (TTF-1/NKX2-1). J Biol Chem. 2012; 287(34):28790-801. PMC: 3436544. DOI: 10.1074/jbc.M112.367987. View

17.

Landa I, Ruiz-Llorente S, Montero-Conde C, Inglada-Perez L, Schiavi F, Leskela S . The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors. PLoS Genet. 2009; 5(9):e1000637. PMC: 2727793. DOI: 10.1371/journal.pgen.1000637. View

18.

Hamdan H, Liu H, Li C, Jones C, Lee M, deLemos R . Structure of the human Nkx2.1 gene. Biochim Biophys Acta. 1998; 1396(3):336-48. DOI: 10.1016/s0167-4781(97)00210-8. View

19.

Bogue C, Ganea G, Sturm E, Ianucci R, Jacobs H . Hex expression suggests a role in the development and function of organs derived from foregut endoderm. Dev Dyn. 2000; 219(1):84-9. DOI: 10.1002/1097-0177(2000)9999:9999<::AID-DVDY1028>3.0.CO;2-5. View

20.

Kershaw R, Siddiqui Y, Roberts D, Jayaraman P, Gaston K . PRH/HHex inhibits the migration of breast and prostate epithelial cells through direct transcriptional regulation of Endoglin. Oncogene. 2013; 33(49):5592-600. DOI: 10.1038/onc.2013.496. View