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Review
. 2021 Apr 20:12:654569.
doi: 10.3389/fendo.2021.654569. eCollection 2021.

Unraveling the Complex Interplay Between Transcription Factors and Signaling Molecules in Thyroid Differentiation and Function, From Embryos to Adults

Arístides López-Márquez  1   2 , Carlos Carrasco-López  1   3 , Celia Fernández-Méndez  1 , Pilar Santisteban  1   3
Affiliations
Review

Unraveling the Complex Interplay Between Transcription Factors and Signaling Molecules in Thyroid Differentiation and Function, From Embryos to Adults

Arístides López-Márquez et al. Front Endocrinol (Lausanne). .

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.

Keywords: development; differentiation; signaling pathways; thyroid; transcription factors.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Stages of early thyroid development. Schematic representation of the main steps of thyroid morphogenesis indicating the corresponding embryonic or post-fertilization day in mice and humans, respectively. From an undifferentiated endoderm, the co-expression of Nkx2-1, Foxe1, Pax8 and Hhex defines the specification of thyroid progenitor cells. Arrows on the left represent the initial stage at which the expression of the thyroid transcription factors and their main target genes are first detected. The onset of thyroid hormone synthesis and Slc5a5 expression occurs at the final stage, once folliculogenesis has occurred and the thyroid gland is completely functional.
Figure 2
Figure 2
Overview of the main players in thyroid follicular cell function. Schematic diagram of a thyroid follicular cell and the main proteins involved in the synthesis, storage, and release into bloodstream of the thyroid hormones triiodothyronine (T3) and thyroxine (T4). At the basolateral membrane, circulating iodide (I-) is actively taken-up by the Nis symporter. It then passively diffuses to the apical membrane where it is actively transported to the lumen by Pendrin and other transporters. Once I- is oxidized by thyroid peroxidase (Tpo), using H2O2 generated by the oxidase Duox2, tyrosine residues in thyroglobulin (Tg) are iodinated to form mono-iodotyrosine (MIT) and/or di-iodotyrosine (DIT), whose coupling yields thyroid hormones. Colloid droplets rich in Tg are endocytosed into the thyroid follicular cell, where Tg lysosomal proteolysis releases MIT, DIT, T4, and T3. Thyroid hormones are transported to circulation by the monocarboxylate transporter 8 (Mct8), whereas I- from MIT and DIT is recycled by the iodotyrosine deiodinase (Dehal1). All of these processes rely on the co-existence of the thyroid transcription factors Nkx2-1, Foxe1, Pax8 and Hhex, in the nucleus of the thyroid follicular cell, from where they regulate the expression of genes such as Slc5a5, Tpo, Tg and Tshr. Also, in the basolateral membrane, TSH, IGF1 and TGFβ trigger the main pathways involved in adult maintenance of thyroid differentiation by cAMP, PI3K and SMAD activation, respectively.
Figure 3
Figure 3
Structure of the promoter regions of the main thyroid differentiation genes. Schematic representation of the main transcription factor binding sites found in the promoter regions of the genes: Thyroglobulin (Tg), Thyroid peroxidase (Tpo), TSH receptor (Tshr) and Sodium/iodide symporter (Nis, Slc5a5). In the case of Slc5a5, the proximal promoter, and the Nis Upstream Enhancer (NUE) are separately indicated. Black arrows represent the transcriptional initiation site of each promoter and numbers define its position. The TATA box is indicated as well as the binding sites for transcription factors: Nkx2-1, Foxe1, Pax8, CREB, CRE-L (CRE-Like) and IRE (Insulin Respose Element).
Figure 4
Figure 4
Thyroid transcription factor crosstalk. Relationship between the four thyroid transcription factors and the thyroid differentiation genes, including the interaction with the novel transcription factors involved in thyroid differentiation. Nkx2-1 is regulated by Taz and Hoxb3 and promotes the expression of the other three TTFs. Pax8 regulates the expression of Hhex and Foxe1 and is positively regulated both by TSH and Taz. It is also negatively regulated by TGFβ. Foxe1 is positively regulated by TSH and IGF1. All four TTFs promote the expression of the thyroid differentiation genes Nis (Slc5a5), Tg and Tpo. The effect of Sox9 and Eya1 remains to be fully elucidated. Pointed arrows denote activation while flat arrows indicate inhibition.
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