GLIS3 and Thyroid: A Pleiotropic Candidate Gene for Congenital Hypothyroidism

Abstract

Variations in the transcription factor Gli-similar 3 (GLIS3) gene have been associated to variable congenital endocrine defects, including both morphogenetic and functional thyroid alterations. Evidence from Glis3 knockout mice indicates a relevant role for GLIS3 in thyroid hormone biosynthesis and postnatal thyroid gland growth, with a mechanism of action downstream of the TSH/TSHR interaction. However, the pathophysiological role of this transcription factor during the embryonic thyroid development remains unexplored. In this manuscript, we will provide an overview of the current knowledge on GLIS3 function during development. As a perspective, we will present preliminary evidence in the zebrafish model in support of a potential role for this pleiotropic transcription factor in the early stages of thyroid gland development.

Keywords: GLIS3; congenital hypothyroidism; sonic hedgehog; thyroid; zebrafish.

Figure 1

(A) Schematic representation of the zebrafish glis3 protein (UniProt F1QB13). Yellow, Serine-Rich (SR) domain; Green, Proline-Rich (PR) domain; Light Blue, Zinc-Finger (ZF) domain; Red, Nuclear Localization Signal (NLS). (B) Alignment of the GLIS3 protein sequencing of the zebrafish (UniProt F1QB13), mouse (UniProt Q0GE24), and human (UniProt Q8NEA6). The color code of the different domains is reported above. The residues that differ between species are highlighted in gray. The missense GLIS3 variants identified in NDH (orange) and CH (green) patients are reported. (C) Aminoacid identity between zebrafish, murine and human GLIS3 proteins, performed using ClustalW2 software.

Figure 2

Ontogenetic pattern of glis3 expression in zebrafish. (A) Tissue specific expression of glis3, at different developmental stages, analyzed by ISH using glis3 antisense riboprobe followed by NBT/BCIP staining, as previously described (29). Images are representative of three experiments (30 embryos each). (B,C) qRT-PCR of glis3 relative mRNA expression during embryonic development and adult tissues. Total RNA is extracted from pools of 50 embryos/stage and from 3 adults, respectively. cDNA synthesis and qRT-PCR following standard procedures (28). Experiments are performed in triplicate and results are expressed by Mean ± SD.