<i>Glis3</i>as a Critical Regulator of Thyroid Primordium Specification

Rurale, Giuditta; Marelli, Federica; Duminuco, Paolo; Persani, Luca

doi:10.1089/thy.2019.0196

Cited by 16 publications

(20 citation statements)

References 55 publications

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“…Knockdown of glis3 in zebrafish embryos also results in thyroid specification defects related to the reduced expression of thyroid markers such as Tg and Nis. Indeed, this model recapitulates thyroid dysgenesis and demonstrates that Glis3 might determine endodermal cell fate by signaling downstream of the Sonic hedgehog (Shh) pathway ( 50 ). Several studies support the role of Glis3 in the Shh pathway.…”

Section: Thyroid Transcription Factorsmentioning

confidence: 98%

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

et al. 2021

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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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Section: Thyroid Transcription Factorsmentioning

confidence: 98%

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

et al. 2021

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“…More recent evidence demonstrates that the down-regulation of GLIS3 in zebra sh embryos leads to thyroid developmental defects. GLIS3 morphants showed a decreased expression of the early transcription factors nkx2.4 and pax2a in the thyroid primordium [28].…”

Section: Discussionmentioning

confidence: 98%

Two novel mutations in Gli-similar 3 in patients with congenital hypothyroidism and thyroid dysgenesis

Lan

Sun²,

Liang

et al. 2021

Preprint

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Background: Thyroid dysgenesis (TD) is the main cause of congenital hypothyroidism (CH). As variants of the transcription factor Gli-similar 3 (GLIS3) have been associated with CH and GLIS3 is one of candidate genes of TD, we screened and characterized GLIS3 mutations in Chinese patients with CH and TD.Methods: To detect mutations, we sequenced all GLIS3 exons in the peripheral blood genomic DNA isolated from 50 patients with TD and 100 healthy individuals. Wild-type and mutant expression vectors of Glis3 were constructed. Quantitative real-time PCR, western blotting, and double luciferase assay were performed to investigation the effect of the mutations on GLIS3 protein function and transcriptional activation.Results: Two novel heterozygous missense mutations, c.2710G>A (p.G904R) and c.2507C>A (p.P836Q), were detected in two unrelated patients. Functional studies revealed that p.G904R expression was 59.95% lower and p.P836Q was 31.23% lower than wild-type GLIS3 mRNA expression. The p.G904R mutation also resulted in lower GLIS3 protein expression compared with that encoded by wild-type GLIS3. Additionally, the luciferase reporter assay revealed that p.G904R mediated impaired transcriptional activation compared with the wild-type protein (p < 0.05) but did not have a dominant-negative effect on the wild-type protein.Conclusions: We for the first time screened and characterized the function of GLIS3 mutations in Chinese individuals with CH and TD. Our study not only broadens the GLIS3 mutation spectrum, but also provides further evidence that GLIS3 defects cause TD.

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“…Interestingly, another associated transcription factor contributing to the Shh pathway-GLIS3 (GLI-Similar protein 3) has recently been demonstrated to influence thyroid development. GLIS3 zebrafish knock-out shows a reduced number of thyroid follicles and an increase of the TSHβ subunit, resembling THA [18]. In humans, homozygous mutations in GLIS3 lead to a multiple malformation syndrome encompassing CH.…”

Section: Discussionmentioning

confidence: 99%

Compound heterozygous GLI3 variants in siblings with thyroid hemiagenesis

et al. 2020

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Purpose Thyroid hemiagenesis (THA) is an inborn absence of one thyroid lobe of largely unknown etiopathogenesis, affecting 0.05-0.5% population. The aim of the study was an identification of genetic factors responsible for thyroid maldevelopment in two siblings with THA. Methods We evaluated a three-generation THA family with two sisters presenting the disorder. Proband (Patient II:3) was diagnosed at the age of 45 due to neck asymmetry. Left lobe agenesis and nontoxic multinodular goiter were depicted. Proband's sister (Patient II:6) was euthyroid, showed up at the age of 39 due to neck discomfort and left-sided THA was demonstrated. Affected individuals were subjected to whole-exome sequencing (WES) (Illumina, TruSeq Exome Kit) and all identified variants were evaluated for pathogenicity. Sanger sequencing was used to confirm WES data and check segregation among first-degree relatives. Results In both siblings, a compound heterozygous mutations NM_000168.6: c.[2179G>A];[4039C>A] (NP_000159.3: p. [Gly727Arg];[Gln1347Lys]) were identified in the GLI3 gene, affecting exon 14 and 15, respectively. According to the American College of Medical Genetics, variants are classified as of uncertain significance, and were found to be very rare (GnomAD MAF 0.007131 and 0.00003187). The segregation mapping and analysis of relatives indicated causativeness of compound heterozygosity. Conclusions We demonstrated for the first time a unique association of THA phenotype and the presence of compound heterozygous mutations p.[Gly727Arg];[Gln1347Lys] of GLI3 gene in two siblings. Keywords Thyroid hemiagenesis • Thyroid dysgenesis • GLI3 gene • GLIS3 gene • Whole-exome sequencing

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Glis3as a Critical Regulator of Thyroid Primordium Specification

Abstract: Thyroid Glis3 as a critical regulator of thyroid primordium specification

Cited by 16 publications

References 55 publications

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

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

Two novel mutations in Gli-similar 3 in patients with congenital hypothyroidism and thyroid dysgenesis

Compound heterozygous GLI3 variants in siblings with thyroid hemiagenesis

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