GLI-Similar 3 (GLIS3) is a member of the GLIS subfamily of Krüppel-like zinc finger transcription factors that functions as an activator or repressor of gene expression. Study of GLIS3-deficiency in mice and humans revealed that GLIS3 plays a critical role in the regulation of several biological processes and is implicated in the development of various diseases, including hypothyroidism and diabetes. This was supported by genome-wide association studies that identified significant associations of common variants in GLIS3 with increased risk of these pathologies. To obtain insights into the causal mechanisms underlying these diseases, it is imperative to understand the mechanisms by which this protein regulates the development of these pathologies. Recent studies of genes regulated by GLIS3 led to the identification of a number of target genes and have provided important molecular insights by which GLIS3 controls cellular processes. These studies revealed that GLIS3 is essential for thyroid hormone biosynthesis and identified a critical function for GLIS3 in the generation of pancreatic β cells and insulin gene transcription. These observations raised the possibility that the GLIS3 signaling pathway might provide a potential therapeutic target in the management of diabetes, hypothyroidism, and other diseases. To develop such strategies, it will be critical to understand the upstream signaling pathways that regulate the activity, expression and function of GLIS3. Here, we review the recent progress on the molecular mechanisms by which GLIS3 controls key functions in thyroid follicular and pancreatic β cells and how this causally relates to the development of hypothyroidism and diabetes.

GLI-Similar 3 (GLIS3) 是 Krüppel 样锌指转录因子 GLIS 亚家族的成员，充当基因表达的激活子或阻遏子。对小鼠和人类 GLIS3 缺陷的研究表明，GLIS3 在多种生物过程的调节中发挥着关键作用，并与多种疾病的发展有关，包括甲状腺功能减退症和糖尿病。全基因组关联研究证实了这一点，该研究发现GLIS3中常见变异与这些病理风险增加之间存在显着关联。为了深入了解这些疾病的因果机制，必须了解该蛋白质调节这些病理学发展的机制。最近对 GLIS3 调节的基因的研究导致了许多靶基因的鉴定，并提供了 GLIS3 控制细胞过程的重要分子见解。这些研究表明，GLIS3 对于甲状腺激素生物合成至关重要，并确定了 GLIS3 在胰腺 β 细胞生成和胰岛素基因转录中的关键功能。这些观察结果表明，GLIS3 信号通路可能为糖尿病、甲状腺功能减退症和其他疾病的治疗提供潜在的治疗靶点。为了制定此类策略，了解调节 GLIS3 活性、表达和功能的上游信号通路至关重要。在此，我们回顾了 GLIS3 控制甲状腺滤泡和胰腺 β 细胞关键功能的分子机制的最新进展，以及其与甲状腺功能减退症和糖尿病的发展之间的因果关系。