Gli-Similar Proteins

Abstract

Gli-similar (Glis) 1–3 proteins constitute a sub-family of Krüppel-like zinc finger proteins that are closely related to members of the Gli family. Glis proteins have been implicated in several pathologies, including cystic kidney disease, diabetes, hypothyroidism, fibrosis, osteoporosis, psoriasis, and cancer. In humans, a mutation in the Glis2 gene has been linked to the development of nephronophthisis (NPHP), a recessive cystic kidney disease, while mutations in Glis3 lead to an extended multi-system phenotype that includes the development of neonatal diabetes, polycystic kidneys, congenital hypothyroidism, and facial dysmorphism. Glis3 has also been identified as a risk locus for type-1 and type-2 diabetes and additional studies have revealed a role for Glis3 in pancreatic endocrine development, β-cell maintenance, and insulin regulation. Similar to Gli1-3, Glis2 and 3 have been reported to localize to the primary cilium. These studies appear to suggest that Glis proteins are part of a primary cilium-associated signaling pathway(s). It has been hypothesized that Glis proteins are activated through post-translational modifications and subsequently translocate to the nucleus where they regulate transcription by interacting with Glis binding sites in the promoter regions of target genes. This chapter will summarize the current state of knowledge regarding mechanisms of action of the Glis family of proteins, their physiological functions, as well as their roles in disease.

GLIS1–3 transcription factors: critical roles in the regulation of multiple physiological processes and diseases

“…GLIS3-deficiency shows some phenotypic variability among patients; some patients do not develop cystic kidneys or skeletal abnormalities or show abnormal thyroid gland development. The phenotypic abnormalities observed in GLIS3-deficient mice largely mimic those observed in human patients [1, 4, 5, 22, 28, 49–51]. …”

“…Insulin ( Ins2 ), cyclin D2 ( Cdnd2 ), fibroblast growth factor 18 ( Fgf18 ), neurogenin 3 ( Ngn3 ), pendrin ( Pds ), and Na + /I - symporter ( Nis ) are among the genes directly regulated by GLIS3, while GLI1 , the Wnt family member 4 ( Wnt4 ) and Snail1 ( Snai1 ) are target genes of GLIS2 [17–22]. The interaction of GLIS proteins with GLISBS is mediated by their ZFD, which consists of a tandem repeat of five C2H2 zinc finger motifs [1, 5, 8, 16, 19]. All five zinc finger motifs are required for optimal binding of GLIS proteins to GLISBS; loss of the first zinc finger has the least impact on this interaction.…”

“…Studies demonstrating that loss of GLIS3 function in humans and mice causes neonatal diabetes indicated a regulatory role for GLIS3 in pancreatic β cells [1, 4, 5, 13, 22, 28, 42–50]. The development of hyperglycemia and hypoinsulinemia in GLIS3 deficiency was found to be related to aberrant pancreatic β cell generation and insulin production suggesting that GLIS3 may have a role in the regulation of pancreas development.…”

“…This was found to be at least in part related to a reduction in the generation of NGN3 + endocrine progenitors during the secondary transition stage (E13.5-E15.5) of pancreas development [5, 14, 28]. The decrease in endocrine progenitors appears to be in part due to suppression of NGN3 expression, a key transcription factor that is required for the commitment of BPs to endocrine progenitors [117, 118, 120].…”

“…GLIS1–3 play a critical role in the regulation of many physiological processes and are been implicated in a variety of pathologies, including neonatal diabetes, glaucoma, cystic kidney disease, neurological disorders, congenital hypothyroidism, and cancer [1, 4, 5, 13, 14]. Study of this subfamily of transcription regulators have provided greater mechanistic insights into the regulation of several physiological processes and the development of various pathologies, and might eventually lead to the discovery of novel therapeutic approaches for these diseases.…”