Journal Article

Sox9 is involved in the thyroid differentiation program and is regulated by crosstalk between TSH, TGFβ and thyroid transcription factors

Santisteban, Pilar, Lemoine, Pascale, Martínez-Cano, Andrea, Pierreux, Christophe E., Carrasco-López, Carlos, López-Márquez, Arístides

2022

Overview

While the signaling pathways and transcription factors involved in the differentiation of thyroid follicular cells, both in embryonic and adult life, are increasingly well understood, the underlying mechanisms and potential crosstalk between the thyroid transcription factors Nkx2.1, Foxe1 and Pax8 and inductive signals remain unclear. Here, we focused on the transcription factor Sox9, which is expressed in Nkx2.1-positive embryonic thyroid precursor cells and is maintained from embryonic development to adulthood, but its function and control are unknown. We show that two of the main signals regulating thyroid differentiation, TSH and TGFβ, modulate Sox9 expression. Specifically, TSH stimulates the cAMP/PKA pathway to transcriptionally upregulate Sox9 mRNA and protein expression, a mechanism that is mediated by the binding of CREB to a CRE site within the Sox9 promoter. Contrastingly, TGFβ signals through Smad proteins to inhibit TSH-induced Sox9 transcription. Our data also reveal that Sox9 transcription is regulated by the thyroid transcription factors, particularly Pax8. Interestingly, Sox9 significantly increased the transcriptional activation of Pax8 and Foxe1 promoters and, consequently, their expression, but had no effect on Nkx2.1 . Our study establishes the involvement of Sox9 in thyroid follicular cell differentiation and broadens our understanding of transcription factor regulation of thyroid function.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/337 / 631/80 / 692/163 / Animals / Cell Differentiation / Cell Line / Cyclic AMP - metabolism / Cyclic AMP response element-binding protein / Cyclic AMP Response Element-Binding Protein - metabolism / Cyclic AMP-Dependent Protein Kinases - metabolism / Embryogenesis / Embryonic growth stage / Forkhead Transcription Factors - genetics / Forkhead Transcription Factors - metabolism / Gene expression / Gene Expression Regulation / Gene regulation / Humanities and Social Sciences / Mice / multidisciplinary / Pax8 protein / PAX8 Transcription Factor - genetics / PAX8 Transcription Factor - metabolism / Promoter Regions, Genetic / Protein kinase A / Science / Science (multidisciplinary) / Signal Transduction / Smad protein / Sox9 protein / SOX9 Transcription Factor - genetics / SOX9 Transcription Factor - metabolism / Thyrocytes / Thyroid / Thyroid Epithelial Cells - cytology / Thyroid Epithelial Cells - metabolism / Thyroid gland / Thyroid Gland - cytology / Thyroid Gland - embryology / Thyroid Gland - metabolism / Thyroid Nuclear Factor 1 - genetics / Thyroid Nuclear Factor 1 - metabolism / Thyroid transcription factor 1 / Thyroid-stimulating hormone / Thyrotropin - metabolism / Thyrotropin - pharmacology / Transcription activation / Transcription factors / Transcription Factors - metabolism / Transcription, Genetic / Transforming Growth Factor beta - metabolism / Transforming Growth Factor beta - pharmacology