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

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 ( ), become also expressed. We further show that KO mice do not display any major changes in prenatal thyroid gland morphology indicating that CH in KO mice is due to dyshormonogenesis rather than thyroid dysgenesis. Analysis of thyroid-specific knockout ( -Pax8Cre) mice fed either a normal or low-iodine diet (ND or LID) revealed that, in contrast to ubiquitous KO 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 KO 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 -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.