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FLASH GENE

Symbol

GLIS3

contributors: mct/pgu - updated : 11-04-2015

HGNC name	GLIS family zinc finger 3
HGNC id	28510

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	NDH neonatal diabetes mellitus and congenital hypothyroidism syndrome
Location	9p24.2      Physical location : 3.824.127 - 4.300.035
Synonym name	zinc finger protein 515
	GLI-similar 3
Synonym symbol(s)	ZNF515, FLJ38999, FLJ90578, MGC33662

DNA

TYPE	functioning gene
STRUCTURE	475.91 kb     11 Exon(s)

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001042413 11 - 7656 NP_001035878 99.4 930 - 2003 14500813 NM_152629 10 - 6672 NP_689842 83.5 775 - 2003 14500813

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive stomach       highly Endocrine pancreas       highly Homo sapiens   thyroid       highly Reproductive female system uterus       Respiratory lung

cells

System Cell Pubmed Species Stage Rna symbol Endocrine islet cell (alpha,beta...) Homo sapiens Skeleton osteoblast Homo sapiens Adult

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

embryo

Text	specific regions in kidney, pancreas and testis

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N terminus playing a critical role in modulating the stability and transcriptional activity of GLIS3 and part of this regulation is mediated through interactions with SUFU and CUL3 within the N terminus
	a DNA binding domain consisting of five C2H2-type zinc finger motifs that share a high degree of homology with members of the GLI and ZIC subfamilies of transcription factors
	a P/LPXY motif in the C terminus, part of the transcription activation domain of GLIS3, and DNA-binding domain and transcriptional activation domain are localized in the center and within the C terminus of GLIS3

HOMOLOGY

interspecies

homolog to murine Glis3 (84.6pc)

Homologene

FAMILY

Krüppel-like family of transcription factors

CATEGORY

regulatory , transcription factor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,cytoskeleton,microtubule
	intracellular,cytoplasm,cytoskeleton,microfilament
	intracellular,nucleus
text	localizes to the primary cilium, suggesting that it is part of a cilium-associated signaling pathway
	upon activation by a primary cilium-associated signaling pathway, GLIS3 is transported by intraflagellar transport into the cytoplasm and subsequently into the nucleus
	GLIS2 and GLIS3 proteins have been demonstrated to localize to the primary cilium, a signaling organelle that has been implicated in several pathologies, including cystic renal diseases
	GLIS3 and SUFU co-localize to the nucleus

basic FUNCTION	acting as a repressor and activator of transcription
	playing a critical role in the regulation of a variety of cellular processes during development
	regulatory role for GLIS3 in osteoblast differentiation
	role of GLIS3 for regulation of insulin gene expression and expands our understanding of its role in the beta cell
	interacts with the transcriptional modulator WWTR1/TAZ, which itself has been implicated in glomerulocystic kidney disease
	plays a key role in pancreatic development, particularly in the generation of beta-cells and in the regulation of insulin gene expression
	essential for the development of pancreatic beta-cells and the maintenance of normal renal functions
	controls potentially fetal islet differentiation via direct transactivation of NEUROG3 1)
	controls beta cell proliferation in response to high-fat feeding at least partly by regulating CCND2 transcription
	normal GLIS3 expression is required for pancreatic beta cell function and mass maintenance during adulthood, which impairment leads to diabetes in adults

CELLULAR PROCESS

nucleotide, transcription, regulation

PHYSIOLOGICAL PROCESS

development

PATHWAY

metabolism

signaling

a component

INTERACTION

DNA

binding

RNA

small molecule	metal binding,
	ions Zn2+

protein	acts synergistically with BMP2 and SHH in inducing osteoblast differentiation
	the promotion of osteoblast differentiation by GLIS3 involves increased expression of FGF18, a positive regulator of osteogenesis
	interacts with and functions as a coactivator of WWTR1(GLIS3 and WWTR1 are part of overlapping transcription regulatory networks that play a critical role in the maintenance of normal renal architecture and function)
	regulate FGF18 (fibroblast growth factor 18) and INS (insulin) gene expression by binding to GlisBS (DNA binding site) within the respective promoters
	interacts with SUFU, which involves a VYGHF motif located within this conserved region
	NDRG1 upregulates neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) and GLI-similar-3 (GLIS3)
	regulates NEUROG3 through its distal promoter region
	can interact directly with ONECUT1 (N-terminus in GLIS3 and the homeodomain of ONECUT1 are critical and this interaction may play an important role in the regulation of NEUROG3 during pancreatic endocrine progenitor cell specification and development)

cell & other

REGULATION

Other

modulation of GLIS3 activity by SUFU and CUL3 may play an important role in the mechanism by which Glis3 regulates the maintenance of pancreatic beta-cell function and insulin gene expression

ASSOCIATED DISORDERS

corresponding disease(s)

NDH

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional       loss of function leads to the development of cystic renal disease, suggesting that it plays a critical role in maintaining normal renal functions constitutional       gain of function involves a primary cilium-associated signal pathway constitutional       loss of function leads to the development of neonatal diabetes and polycystic kidney disease

Susceptibility

to type 2 diabetes to decreased glucose-stimulated insulin response

Variant & Polymorphism SNP	rs7034200 displayed evidence for association with type 2 diabetes
	variants at the DGKB/AGMO, ADRA2A, GLIS3 and C2CD4B loci were associated with decreased glucose-stimulated insulin response

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS

	Glis3 mutant mice exhibit abnormalities very similar to those displayed by NDH1 patients,
	including a greatly reduced life span and development of polycystic kidneys and neonatal diabetes