A Neonate With Diabetes Mellitus, Congenital Hypothyroidism, and Congenital Glaucoma

Boddu, Praveen Kumar; Velumula, Pradeep Kumar; Sharif, Saima; Monika, Bajaj

doi:10.7759/cureus.29488

Cited by 2 publications

(1 citation statement)

References 13 publications

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“…Krüppel-like zinc nger protein, GLI-Similar 3 (GLIS3), was recently identi ed as a critical regulator of thyroid follicular cell functions [14,15]. Loss-of-function mutations in human GLIS3 cause a syndrome characterized by neonatal diabetes and congenital hypothyroidism (NDH) [16][17][18][19][20][21][22][23][24], while single nucleotide polymorphisms in GLIS3 are associated with thyroid dysfunction and increased risk of CH [25][26][27][28][29][30][31][32]. Ubiquitous Glis3 knockout (Glis3KO) mice exhibit a very similar phenotype as human NDH patients, including the development of neonatal diabetes and CH [33,34].…”

Section: Introductionmentioning

confidence: 99%

Role of GLIS3 in thyroid development and in the regulation of gene expression in thyroid specific Glis3KO mice

Kang

Grimm

Liao

et al. 2023

Preprint

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Loss of GLI-Similar 3 (GLIS3) function in mice and humans causes congenital hypothyroidism (CH). In this study, we demonstrate that GLIS3 protein is first detectable at E15.5 of murine thyroid development, a time when GLIS3 target genes, such as Slc5a5 (Nis), become also expressed. We further show that Glis3KO mice do not display any major changes in prenatal thyroid gland morphology indicating that CH in Glis3KO mice is due to dyshormonogenesis rather than thyroid dysgenesis. Analysis of thyroid-specific Glis3 knockout (Glis3-Pax8Cre) mice fed either a normal or low-iodine diet (ND or LID) revealed that, in contrast to ubiquitous Glis3KO mice, thyroid follicular cell proliferation and the expression of cell cycle genes were not repressed suggesting that the inhibition of thyroid follicular cell proliferation in ubiquitous Glis3KO mice is related to loss of GLIS3 function in other cell types. However, the expression of several thyroid hormone biosynthesis-, extracellular matrix (ECM)-, and inflammation-related genes was still suppressed in Glis3-Pax8Cre mice particularly under conditions of high blood levels of thyroid stimulating hormone (TSH). We further demonstrate that treatment with TSH, protein kinase A (PKA) or adenylyl cyclase activators or expression of constitutively active PKA enhances GLIS3 protein and activity, suggesting that GLIS3 transcriptional activity is regulated in part by TSH/TSHR-mediated activation of the PKA pathway. This mechanism of regulation provides an explanation for the dramatic increase in GLIS3 protein expression and the subsequent induction of GLIS3 target genes, including several thyroid hormone biosynthetic genes, in thyroid follicular cells of mice fed a LID.

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Section: Introductionmentioning

confidence: 99%

Role of GLIS3 in thyroid development and in the regulation of gene expression in thyroid specific Glis3KO mice

Kang

Grimm

Liao

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

GLIS3 expression in the thyroid gland in relation to TSH signaling and regulation of gene expression

Kang,

Grimm,

Liao

et al. 2024

Cell. Mol. Life Sci.

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Loss of GLI-Similar 3 (GLIS3) function in mice and humans causes congenital hypothyroidism (CH). In this study, we demonstrate that GLIS3 protein is first detectable at E15.5 of murine thyroid development, a time at which GLIS3 target genes, such as Slc5a5 (Nis), become expressed. This, together with observations showing that ubiquitous Glis3KO mice do not display major changes in prenatal thyroid gland morphology, indicated that CH in Glis3KO mice is due to dyshormonogenesis rather than thyroid dysgenesis. Analysis of GLIS3 in postnatal thyroid suggested a link between GLIS3 protein expression and blood TSH levels. This was supported by data showing that treatment with TSH, cAMP, or adenylyl cyclase activators or expression of constitutively active PKA enhanced GLIS3 protein stability and transcriptional activity, indicating that GLIS3 activity is regulated at least in part by TSH/TSHR-mediated activation of PKA. The TSH-dependent increase in GLIS3 transcriptional activity would be critical for the induction of GLIS3 target gene expression, including several thyroid hormone (TH) biosynthetic genes, in thyroid follicular cells of mice fed a low iodine diet (LID) when blood TSH levels are highly elevated. Like TH biosynthetic genes, the expression of cell cycle genes is suppressed in ubiquitous Glis3KO mice fed a LID; however, in thyroid-specific Glis3 knockout mice, the expression of cell cycle genes was not repressed, in contrast to TH biosynthetic genes. This indicated that the inhibition of cell cycle genes in ubiquitous Glis3KO mice is dependent on changes in gene expression in GLIS3 target tissues other than the thyroid.

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A Neonate With Diabetes Mellitus, Congenital Hypothyroidism, and Congenital Glaucoma

Cited by 2 publications

References 13 publications

Role of GLIS3 in thyroid development and in the regulation of gene expression in thyroid specific Glis3KO mice

Role of GLIS3 in thyroid development and in the regulation of gene expression in thyroid specific Glis3KO mice

GLIS3 expression in the thyroid gland in relation to TSH signaling and regulation of gene expression

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