The Krüppel-like zinc finger protein GLIS3 transactivates neurogenin 3 for proper fetal pancreatic islet differentiation in mice

Abstract

Aims/hypothesis Mutations in GLIS3, which encodes a Krüppel-like zinc finger transcription factor, were found to underlie sporadic neonatal diabetes. Inactivation of Glis3 by gene targeting in mice was previously shown to lead to neonatal diabetes, but the underlying mechanism remains largely unknown. We aimed to elucidate the mechanism of action of GLIS family zinc finger 3 (GLIS3) in Glis3−/− mice and to further decipher its action in in-vitro systems. Methods We created Glis3−/− mice and monitored the morphological and biochemical phenotype of their pancreatic islets at different stages of embryonic development. We combined these observations with experiments on Glis3 expressed in cultured cells, as well as in in vitro systems in the presence of other reconstituted components. Results In vivo and in vitro analyses placed Glis3 upstream of Neurog3, the endocrine pancreas lineage-defining transcription factor. We found that GLIS3 binds to specific GLIS3-response elements in the Neurog3 promoter, activating Neurog3 gene transcription both directly, and synergistically with hepatic nuclear factor 6 and forkhead box A2. Conclusions/interpretation These results indicate that GLIS3 controls fetal islet differentiation via direct transactivation of Neurog3, a perturbation that causes neonatal diabetes in mice.

GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation

“…Similar phenotypes have been observed in Glis3-deficient mice (29)(30)(31)(32)(33)(34)(35). Recently, an association was found between GLIS3 variants and congenital hypothyroidism (36).…”

Hnf1b controls pancreas morphogenesis and the generation of Ngn3+ endocrine progenitors

“…By E17.5, Hnf1b expression is partially restored and reduction of Ngn3 + cells is clearly less pronounced when compared with earlier time points, supporting the notion that downregulation of Hnf1b in Hnf6 mutants might be important for Ngn3 downregulation (Maestro et al, 2003). Pdx1 also contributes to Ngn3 regulation and, together with Hnf6 (Oliver-Krasinski et al, 2009) and Glis3 (Kim et al, 2012;Yang et al, 2011), occupies an evolutionary conserved enhancer homologous to human cluster 1 (Lee et al, 2001). Ngn3 cluster 1 RESEARCH ARTICLE Development (2015) 142, 871-882 doi:10.1242 also contains putative Sox9-binding sites (at −3.3 kb), which were occupied by Sox9 in ChIP experiments on mPAC ductal cells (Lynn et al, 2007).…”

“…Ngn3 cluster 1 RESEARCH ARTICLE Development (2015) 142, 871-882 doi:10.1242 also contains putative Sox9-binding sites (at −3.3 kb), which were occupied by Sox9 in ChIP experiments on mPAC ductal cells (Lynn et al, 2007). However, ChIP on embryonic pancreata demonstrated that Sox9 was not bound to cluster 1, but to three other regions: one distal (at −4.0 kb) and two proximal (at −0.4 kb and −161 bp) (Seymour et al, 2008 (Ejarque et al, 2013), whereas this factor was able to activate the Ngn3 full promoter (−5800 to +40 bp) (Yang et al, 2011), suggesting that the Hnf1b-binding site we identified at −4890 bp might be important for Ngn3 activation. These studies support the existence of distinct enhancer modules with differential binding of essential transcription factors that contribute to the activation of Ngn3.…”

Transcription factor regulation of pancreatic organogenesis, differentiation and maturation

“…Involved in b-cell development and insulin expression [200][201][202] enhancer. 79 Endoderm-specific ablation of Foxa2 in mice induced extreme hypoglycemia and early death (Table 1).…”

“…198,199 Glis3 knockout mice produce pups with neonatal diabetes presenting with hyperglycemia and hypoinsulinemia that die shortly after birth (Table 1). [200][201][202] These pups have diminished b-cells. Glis3 has also been shown to regulate insulin expression in mature b-cells.…”