Cited by 49Thyroid Disorders and TreatmentsDevelopmental Biology and Gene RegulationThyroid Cancer Diagnosis and Treatment

Unraveling the complex interplay between transcription factors and signaling molecules in thyroid differentiation and function, from embryos to adults

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López-Márquez, Arístides, Carrasco-López, Carlos, Fernández-Méndez, Celia, Santisteban, Pilar·2021·Frontiers in Endocrinology

Abstract

Thyroid differentiation of progenitor cells occurs during embryonic development and in the adult thyroid gland, and the molecular bases of these complex and finely regulated processes are becoming ever more clear. In this Review , we describe the most recent advances in the study of transcription factors, signaling molecules and regulatory pathways controlling thyroid differentiation and development in the mammalian embryo. We also discuss the maintenance of the adult differentiated phenotype to ensure the biosynthesis of thyroid hormones. We will focus on endoderm-derived thyroid epithelial cells, which are responsible for the formation of the thyroid follicle, the functional unit of the thyroid gland. The use of animal models and pluripotent stem cells has greatly aided in providing clues to the complicated puzzle of thyroid development and function in adults. The so-called thyroid transcription factors – Nkx2-1, Foxe1, Pax8 and Hhex – were the first pieces of the puzzle identified in mice. Other transcription factors, either acting upstream of or directly with the thyroid transcription factors, were subsequently identified to, almost, complete the puzzle. Among them, the transcription factors Glis3, Sox9 and the cofactor of the Hippo pathway Taz, have emerged as important players in thyroid differentiation and development. The involvement of signaling molecules increases the complexity of the puzzle. In this context, the importance of Bmps, Fgfs and Shh signaling at the onset of development, and of TSH, IGF1 and TGFβ both at the end of terminal differentiation in embryos and in the adult thyroid, are well recognized. All of these aspects are covered herein. Thus, readers will be able to visualize the puzzle of thyroid differentiation with most – if not all – of the pieces in place.

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Crossref · 10.3389/fendo.2021.654569

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  • The DNA binding sites of TTF1 and PAX8 often colocalize in the promoters of target genes.

    “the DNA binding sites of TTF1 and PAX8 often colocalize in the promoters of target genes (143).”

    From Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion (2022) · cites this paper as [143]

    The Regulation of Thyroid Differentiation Genes section (page unavailable) says thyroid transcription factors bind consensus sites within target promoters, and the References list cites a study of TTF1 and PAX8 synergistically activating the thyroglobulin promoter. Neither passage says their DNA-binding sites colocalize or that this occurs often across target-gene promoters. (LLM, conf=0.78)

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  1. [134]Leoni SG Sastre-Perona A De la Vieja A Santisteban P. Selenium Increases Thyroid-Stimulating Hormone-Induced Sodium/Iodide Symporter Expression Through Thioredoxin/Apurinic/Apyrimidinic Endonuclease 1-Dependent Regulation of Paired Box 8 Binding Activity. Antioxid Redox Signal (2009) 24(15): 855–66. 10.1089/ars.2014.6228 26650895 · DOI

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Authors
López-Márquez, A., Carrasco-López, C., Fernández-Méndez, C., & Santisteban, P.
Affiliations
Consejo Superior de Investigaciones Científicas (ES)
Corresponding author
Santisteban, Pilar
Venue
Frontiers in Endocrinology
Published
2021-04-20
Volume
12
Pages
654569-654569
ISSN
1664-2392 (ISSN-L)
OpenAlex
W3153037559
Cited by
49
References
170
Citations by year
2026: 15 · 2025: 4 · 2024: 9 · 2023: 11 · 2022: 9 · 2021: 1
FWCI
1.14
Type
journal article
Language
en
Open access
Locations
  • Frontiers in Endocrinology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Comunidad de Madrid (S2017/BMD-3724, S2017/BMD, GCB14142311CRES, BMD-3724)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
Keywords
thyroid development, thyroid differentiation, thyroid transcription factors, TTF-1, FOXE1, PAX8, HHEX, GLIS3, SOX9, TAZ, Hippo signaling pathway, BMP signaling, FGF signaling, Sonic hedgehog signaling, TSH signaling, insulin-like growth factor I, TGF-beta, thyroid hormone synthesis, thyroid follicles, pluripotent stem cells, mouse model
MeSH terms
PAX8 Transcription Factor, Thyroid Epithelial Cells, Thyroid Nuclear Factor 1, Hippo Signaling Pathway, Animals, Cell Differentiation, Endoderm, Humans, Stem Cells, Thyroid Gland, Transcription Factors, Signal Transduction, Trans-Activators, Homeodomain Proteins, Gene Expression Regulation, Developmental, Mice, Forkhead Transcription Factors

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