GLI3

Last updated
GLI3
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases GLI3 , ACLS, GCPS, GLI3-190, GLI3FL, PAP-A, PAPA, PAPA1, PAPB, PHS, PPDIV, GLI family zinc finger 3
External IDs OMIM: 165240 MGI: 95729 HomoloGene: 139 GeneCards: GLI3
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000168

NM_008130

RefSeq (protein)

NP_000159

NP_032156

Location (UCSC) Chr 7: 41.96 – 42.26 Mb Chr 13: 15.64 – 15.9 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Zinc finger protein GLI3 is a protein that in humans is encoded by the GLI3 gene. [5] [6]

Contents

This gene encodes a protein that belongs to the C2H2-type zinc finger proteins subclass of the Gli family. They are characterized as DNA-binding transcription factors and are mediators of Sonic hedgehog (Shh) signaling. The protein encoded by this gene localizes in the cytoplasm and activates patched Drosophila homolog (PTCH1) gene expression. It is also thought to play a role during embryogenesis. [6]

Role in development

Gli3 is a known transcriptional repressor but may also have a positive transcriptional function. [7] [8] Gli3 represses dHand and Gremlin, which are involved in developing digits. [9] There is evidence that Shh-controlled processing (e.g., cleavage) regulates transcriptional activity of Gli3 similarly to that of Ci. [8] Gli3 mutant mice have many abnormalities including CNS and lung defects and limb polydactyly. [10] [11] [12] [13] [14] In the developing mouse limb bud, Gli3 derepression predominantly regulates Shh target genes. [15]

Disease association

Mutations in this gene have been associated with several diseases, including Greig cephalopolysyndactyly syndrome, Pallister–Hall syndrome, preaxial polydactyly type IV, and postaxial polydactyly types A1 and B. [6] DNA copy-number alterations that contribute to increased conversion of the oncogenes Gli1–3 into transcriptional activators by the Hedgehog signaling pathway are included in a genome-wide pattern, which was found to be correlated with an astrocytoma patient's outcome. [16] [17]

There is evidence that the autosomal dominant disorder Greig cephalopolysyndactyly syndrome (GCPS) that affects limb and craniofacial development in humans is caused by a translocations within the GLI3 gene. [18]

Interactions with Gli1 and Gli2

The independent overexpression Gli1 and Gli2 in mice models to lead to formation of basal cell carcinoma (BCC). Gli1 knockout is shown to lead to similar embryonic malformations as Gli1 overexpressions but not the formation of BCCs. Overexpression of Gli3 in transgenic mice and frogs does not lead to the development of BCC-like tumors and is not thought to play a role in tumor BCC formation. [19]

Gli1 and Gli2 overexpression leads to BCC formation in mouse models and a one step model for tumour formation has been suggested in both cases. This also indicates that Gli1 and/or Gli2 overexpression is vital in BCC formation. Co-overexpression of Gli1 with Gli2 and Gli2 with Gli3 leads to transgenic mice malformations and death, respectively, but not the formation of BCC. This suggests that overexpression of more than one Gli protein is not necessary for BCC formation.

Interactions

GLI3 has been shown to interact with CREBBP [20] SUFU, [21] ZIC1, [22] and ZIC2. [22]

Related Research Articles

<span class="mw-page-title-main">Sonic hedgehog protein</span> Signaling molecule in animals

Sonic hedgehog protein(SHH) is encoded for by the SHH gene. The protein is named after the character Sonic the Hedgehog.

<span class="mw-page-title-main">GLI1</span> Protein-coding gene in humans

Zinc finger protein GLI1 also known as glioma-associated oncogene is a protein that in humans is encoded by the GLI1 gene. It was originally isolated from human glioblastoma cells.

<span class="mw-page-title-main">GLI2</span> Protein-coding gene in the species Homo sapiens

Zinc finger protein GLI2 also known as GLI family zinc finger 2 is a protein that in humans is encoded by the GLI2 gene. The protein encoded by this gene is a transcription factor.

<span class="mw-page-title-main">Greig cephalopolysyndactyly syndrome</span> Medical condition

Greig cephalopolysyndactyly syndrome is a disorder that affects development of the limbs, head, and face. The features of this syndrome are highly variable, ranging from very mild to severe. People with this condition typically have one or more extra fingers or toes (polydactyly) or an abnormally wide thumb or big toe (hallux).

<span class="mw-page-title-main">Pallister–Hall syndrome</span> Medical condition

Pallister–Hall syndrome (PHS) is a rare genetic disorder that affects various body systems. The main features are a non-cancerous mass on the hypothalamus and extra digits (polydactylism). The prevalence of Pallister-Hall Syndrome is unknown; about 100 cases have been reported in publication.

The Hedgehog signaling pathway is a signaling pathway that transmits information to embryonic cells required for proper cell differentiation. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The pathway also has roles in the adult. Diseases associated with the malfunction of this pathway include cancer.

<span class="mw-page-title-main">Limb development</span>

Limb development in vertebrates is an area of active research in both developmental and evolutionary biology, with much of the latter work focused on the transition from fin to limb.

Gremlin is an inhibitor in the TGF beta signaling pathway. It primarily inhibits bone morphogenesis and is implicated in disorders of increased bone formation and several cancers.

<span class="mw-page-title-main">STIL</span> Protein-coding gene in the species Homo sapiens

SCL-interrupting locus protein is a protein that in humans is encoded by the STIL gene. STIL is present in many different cell types and is essential for centriole biogenesis. This gene encodes a cytoplasmic protein implicated in regulation of the mitotic spindle checkpoint, a regulatory pathway that monitors chromosome segregation during cell division to ensure the proper distribution of chromosomes to daughter cells. The protein is phosphorylated in mitosis and in response to activation of the spindle checkpoint, and disappears when cells transition to G1 phase. It interacts with a mitotic regulator, and its expression is required to efficiently activate the spindle checkpoint.

<span class="mw-page-title-main">LMBR1</span> Protein-coding gene in the species Homo sapiens

Limb region 1 protein homolog is a protein that in humans is encoded by the LMBR1 gene.

<span class="mw-page-title-main">TBX2</span> Protein-coding gene in the species Homo sapiens

T-box transcription factor 2 Tbx2 is a transcription factor that is encoded by the Tbx2 gene on chromosome 17q21-22 in humans. This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. Tbx2 and Tbx3 are the only T-box transcription factors that act as transcriptional repressors rather than transcriptional activators, and are closely related in terms of development and tumorigenesis. This gene plays a significant role in embryonic and fetal development through control of gene expression, and also has implications in various cancers. Tbx2 is associated with numerous signaling pathways, BMP, TGFβ, Wnt, and FGF, which allow for patterning and proliferation during organogenesis in fetal development.

<span class="mw-page-title-main">SUFU</span> Protein-coding gene in the species Homo sapiens

Suppressor of fused homolog is a protein that in humans is encoded by the SUFU gene. In molecular biology, the protein domain suppressor of fused protein (Sufu) has an important role in the cell. The Sufu is important in negatively regulating an important signalling pathway in the cell, the Hedgehog signalling pathway (HH). This particular pathway is crucial in embryonic development. There are several homologues of Sufu, found in a wide variety of organisms.

<span class="mw-page-title-main">ZIC3</span> Protein-coding gene in the species Homo sapiens

ZIC3 is a member of the Zinc finger of the cerebellum (ZIC) protein family.

<span class="mw-page-title-main">ZIC2</span> Protein-coding gene in the species Homo sapiens

Zinc finger protein ZIC2 is a protein that in humans is encoded by the ZIC2 gene. ZIC2 is a member of the Zinc finger of the cerebellum (ZIC) protein family.

<span class="mw-page-title-main">ALX4</span> Protein-coding gene in the species Homo sapiens

Homeobox protein aristaless-like 4 is a protein that in humans is encoded by the ALX4 gene. Alx4 belongs to the group-1 aristaless-related genes, a majority of which are linked to the development of the craniofacial and/or appendicular skeleton, along with PRRX1, SHOX, ALX3, and CART1. The Alx4 protein acts as a transcriptional activator and is predominantly expressed in the mesenchyme of the developing embryonic limb buds. Transcripts of this gene are detectable in the lateral plate mesoderm just prior to limb induction. Alx4 expression plays a major role in the determination of spatial orientation of the growing limb bud by aiding in the establishment of anteroposterior polarity of the limb. It does this by working in conjunction with Gli3 and dHand to restrict the expression of Sonic Hedgehog (SHh) to the posterior mesenchyme, which will eventually give rise to the Zone of Polarizing Activity (ZPA). This gene has been proven to be allelic with mutations and deletions giving rise to a host of craniofacial dismorphologies and several forms of polydactyly in mammalian development. A mouse-model knockout of this gene, dubbed Strong's luxoid, was originally created by Forstheofel in the 1960s and has been extensively studied to understand the partial and complete loss-of-function properties of this gene.

<span class="mw-page-title-main">Acrocallosal syndrome</span> Medical condition

Acrocallosal syndrome is an extremely rare autosomal recessive syndrome characterized by corpus callosum agenesis, polydactyly, multiple dysmorphic features, motor and intellectual disabilities, and other symptoms. The syndrome was first described by Albert Schinzel in 1979. Mutations in KIF7 are causative for ACLS, and mutations in GLI3 are associated with a similar syndrome.

<span class="mw-page-title-main">Zone of polarizing activity</span>

The zone of polarizing activity (ZPA) is an area of mesenchyme that contains signals which instruct the developing limb bud to form along the anterior/posterior axis. Limb bud is undifferentiated mesenchyme enclosed by an ectoderm covering. Eventually, the limb bud develops into bones, tendons, muscles and joints. Limb bud development relies not only on the ZPA, but also many different genes, signals, and a unique region of ectoderm called the apical ectodermal ridge (AER). Research by Saunders and Gasseling in 1948 identified the AER and its subsequent involvement in proximal distal outgrowth. Twenty years later, the same group did transplantation studies in chick limb bud and identified the ZPA. It wasn't until 1993 that Todt and Fallon showed that the AER and ZPA are dependent on each other.

<span class="mw-page-title-main">Bat wing development</span>

The order Chiroptera, comprising all bats, has evolved the unique mammalian adaptation of flight. Bat wings are modified tetrapod forelimbs. Because bats are mammals, the skeletal structures in their wings are morphologically homologous to the skeletal components found in other tetrapod forelimbs. Through adaptive evolution these structures in bats have undergone many morphological changes, such as webbed digits, elongation of the forelimb, and reduction in bone thickness. Recently, there have been comparative studies of mouse and bat forelimb development to understand the genetic basis of morphological evolution. Consequently, the bat wing is a valuable evo-devo model for studying the evolution of vertebrate limb diversity.

<span class="mw-page-title-main">Polysyndactyly</span> Medical condition

Polysyndactyly is a congenital anomaly, combining polydactyly and syndactyly, in which affected individuals have an extra finger or toe that is connected, via fusing or webbing, to an adjacent digit.

<span class="mw-page-title-main">TBX15</span> Protein-coding gene in the species Homo sapiens

T-box transcription factor TBX15 is protein that is encoded in humans by the Tbx15 gene, mapped to Chromosome 3 in mice and Chromosome 1 in humans. Tbx15 is a transcription factor that plays a key role in embryonic development. Like other members of the T-box subfamily, Tbx15 is expressed in the notochord and primitive streak, where it assists with the formation and differentiation of the mesoderm. It is steadily downregulated after segmentation of the paraxial mesoderm.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000106571 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000021318 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Ruppert JM, Vogelstein B, Arheden K, Kinzler KW (October 1990). "GLI3 encodes a 190-kilodalton protein with multiple regions of GLI similarity". Molecular and Cellular Biology. 10 (10): 5408–15. doi:10.1128/mcb.10.10.5408. PMC   361243 . PMID   2118997.
  6. 1 2 3 "Entrez Gene: GLI3 GLI-Kruppel family member GLI3 (Greig cephalopolysyndactyly syndrome)".
  7. Taipale J, Beachy PA (May 2001). "The Hedgehog and Wnt signalling pathways in cancer". Nature. 411 (6835): 349–54. Bibcode:2001Natur.411..349T. doi:10.1038/35077219. PMID   11357142. S2CID   4414768.
  8. 1 2 Jacob J, Briscoe J (August 2003). "Gli proteins and the control of spinal-cord patterning". EMBO Reports. 4 (8): 761–5. doi:10.1038/sj.embor.embor896. PMC   1326336 . PMID   12897799.
  9. te Welscher P, Fernandez-Teran M, Ros MA, Zeller R (February 2002). "Mutual genetic antagonism involving GLI3 and dHAND prepatterns the vertebrate limb bud mesenchyme prior to SHH signaling". Genes & Development. 16 (4): 421–6. doi:10.1101/gad.219202. PMC   155343 . PMID   11850405.
  10. Rash BG, Grove EA (October 2007). "Patterning the dorsal telencephalon: a role for sonic hedgehog?". The Journal of Neuroscience. 27 (43): 11595–603. doi: 10.1523/jneurosci.3204-07.2007 . PMC   6673221 . PMID   17959802.
  11. Franz T (1994). "Extra-toes (Xt) homozygous mutant mice demonstrate a role for the Gli-3 gene in the development of the forebrain". Acta Anatomica. 150 (1): 38–44. doi:10.1159/000147600. PMID   7976186.
  12. Grove EA, Tole S, Limon J, Yip L, Ragsdale CW (June 1998). "The hem of the embryonic cerebral cortex is defined by the expression of multiple Wnt genes and is compromised in Gli3-deficient mice". Development. 125 (12): 2315–25. doi:10.1242/dev.125.12.2315. PMID   9584130.
  13. Hui CC, Joyner AL (March 1993). "A mouse model of greig cephalopolysyndactyly syndrome: the extra-toesJ mutation contains an intragenic deletion of the Gli3 gene". Nature Genetics. 3 (3): 241–6. doi:10.1038/ng0393-241. PMID   8387379. S2CID   345712.
  14. Schimmang T, Lemaistre M, Vortkamp A, Rüther U (November 1992). "Expression of the zinc finger gene Gli3 is affected in the morphogenetic mouse mutant extra-toes (Xt)". Development. 116 (3): 799–804. doi:10.1242/dev.116.3.799. PMID   1289066.
  15. Lewandowski JP, Du F, Zhang S, Powell MB, Falkenstein KN, Ji H, Vokes SA (Oct 2015). "Spatiotemporal regulation of GLI target genes in the mammalian limb bud". Dev. Biol. 406 (1): 92–103. doi:10.1016/j.ydbio.2015.07.022. PMC   4587286 . PMID   26238476.
  16. Aiello KA, Ponnapalli SP, Alter O (September 2018). "Mathematically universal and biologically consistent astrocytoma genotype encodes for transformation and predicts survival phenotype". APL Bioengineering. 2 (3): 031909. doi:10.1063/1.5037882. PMC   6215493 . PMID   30397684.
  17. Aiello KA, Alter O (October 2016). "Platform-Independent Genome-Wide Pattern of DNA Copy-Number Alterations Predicting Astrocytoma Survival and Response to Treatment Revealed by the GSVD Formulated as a Comparative Spectral Decomposition". PLOS ONE. 11 (10): e0164546. Bibcode:2016PLoSO..1164546A. doi: 10.1371/journal.pone.0164546 . PMC   5087864 . PMID   27798635.
  18. Böse J, Grotewold L, Rüther U (May 2002). "Pallister-Hall syndrome phenotype in mice mutant for Gli3". Human Molecular Genetics. 11 (9): 1129–35. doi: 10.1093/hmg/11.9.1129 . PMID   11978771.
  19. Dahmane N, Lee J, Robins P, Heller P, Ruiz i Altaba A (October 1997). "Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours". Nature. 389 (6653): 876–81. Bibcode:1997Natur.389..876D. doi:10.1038/39918. PMID   9349822. S2CID   4424572.
  20. Dai P, Akimaru H, Tanaka Y, Maekawa T, Nakafuku M, Ishii S (March 1999). "Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3". The Journal of Biological Chemistry. 274 (12): 8143–52. doi: 10.1074/jbc.274.12.8143 . PMID   10075717.
  21. Humke EW, Dorn KV, Milenkovic L, Scott MP, Rohatgi R (April 2010). "The output of Hedgehog signaling is controlled by the dynamic association between Suppressor of Fused and the Gli proteins". Genes & Development. 24 (7): 670–82. doi:10.1101/gad.1902910. PMC   2849124 . PMID   20360384.
  22. 1 2 Koyabu Y, Nakata K, Mizugishi K, Aruga J, Mikoshiba K (March 2001). "Physical and functional interactions between Zic and Gli proteins". The Journal of Biological Chemistry. 276 (10): 6889–92. doi: 10.1074/jbc.C000773200 . PMID   11238441.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.