GLIS1

Abstract: In this study, we describe the identification and characterization of a novel transcription factor GLI-similar 3 (GLIS3). GLIS3 is an 83.8 kDa nuclear protein containing five C2H2-type Kruppel-like zinc finger motifs that exhibit 93% identity with those of GLIS1, however, little homology exists outside their zinc finger domains. GLIS3 can function as a repressor and activator of transcription. Deletion mutant analysis determined that the N- and C-termini are required for optimal transcriptional activity. GLIS3 binds to the GLI-RE consensus sequence and is able to enhance GLI-RE-dependent transcription. GLIS3(DeltaC496), a dominant-negative mutant, inhibits transcriptional activation by GLIS3 and GLI1. Whole mount in situ hybridization on mouse embryos from stage E6.5 through E14.5 demonstrated that GLIS3 is expressed in specific regions in developing kidney and testis and in a highly dynamic pattern during neurulation. From E11.5 through E12.5 GLIS3 was strongly expressed in the interdigital regions, which are fated to undergo apoptosis. The temporal and spatial pattern of GLIS3 expression observed during embryonic development suggests that it may play a critical role in the regulation of a variety of cellular processes during development. Both the repressor and activation functions of GLIS3 may be involved in this control.

Abstract: Kruppel-like zinc finger proteins form one of the largest families of transcription factors. They function as key regulators of embryonic development and a wide range of other physiological processes, and are implicated in a variety of pathologies. GLI-similar 1-3 (GLIS1-3) constitute a subfamily of Kruppel-like zinc finger proteins that act either as activators or repressors of gene transcription. GLIS3 plays a critical role in the regulation of multiple biological processes and is a key regulator of pancreatic β cell generation and maturation, insulin gene expression, thyroid hormone biosynthesis, spermatogenesis, and the maintenance of normal kidney functions. Loss of GLIS3 function in humans and mice leads to the development of several pathologies, including neonatal diabetes and congenital hypothyroidism, polycystic kidney disease, and infertility. Single nucleotide polymorphisms in GLIS3 genes have been associated with increased risk of several diseases, including type 1 and type 2 diabetes, glaucoma, and neurological disorders. GLIS2 plays a critical role in the kidney and GLIS2 dysfunction leads to nephronophthisis, an end-stage, cystic renal disease. In addition, GLIS1-3 have regulatory functions in several stem/progenitor cell populations. GLIS1 and GLIS3 greatly enhance reprogramming efficiency of somatic cells into induced embryonic stem cells, while GLIS2 inhibits reprogramming. Recent studies have obtained substantial mechanistic insights into several physiological processes regulated by GLIS2 and GLIS3, while a little is still known about the physiological functions of GLIS1. The localization of some GLIS proteins to the primary cilium suggests that their activity may be regulated by a downstream primary cilium-associated signaling pathway. Insights into the upstream GLIS signaling pathway may provide opportunities for the development of new therapeutic strategies for diabetes, hypothyroidism, and other diseases.

Abstract: Recent studies have provided evidence for a regulatory role of GLI-similar (GLIS) transcription factors in reprogramming, maintenance and differentiation of several stem and progenitor cell populations. GLIS1, in conjunction with several other reprogramming factors, was shown to markedly increase the efficiency of generating induced pluripotent stem cells (iPSC) from somatic cells. GLIS2 has been reported to contribute to the maintenance of the pluripotent state in hPSCs. In addition, GLIS2 has a function in regulating self-renewal of hematopoietic progenitors and megakaryocytic differentiation. GLIS3 plays a critical role during the development of several tissues. GLIS3 is able to promote reprogramming of human fibroblasts into retinal pigmented epithelial (RPE) cells. Moreover, GLIS3 is essential for spermatogonial stem cell renewal and spermatogonial progenitor cell differentiation. During pancreas development, GLIS3 protein is first detectable in bipotent pancreatic progenitors and pro-endocrine progenitors and plays a critical role in the generation of pancreatic beta cells. Here, we review the current status of the roles of GLIS proteins in the maintenance and differentiation of these different stem and progenitor cells.