Home LiteratureArticle Details
PMID: 14581620 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Loss-of-function mutations in the human GLI2 gene are associated with pituitary anomalies and holoprosencephaly-like features.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 100 ·No. 23 ·2003-11-11 ·Pages 13424-9

Roessler E, Du YZ, Mullor JL, Casas E, Allen WP, Gillessen-Kaesbach G, Roeder ER, Ming JE, Ruiz i Altaba A, Muenke M

Abstract

Diminished Sonic Hedgehog (Shh) signaling is associated with the most common forebrain defect in humans, holoprosencephaly (HPE), which includes cyclopia, a phenotype also seen in mice and other vertebrates with defective Shh signaling. The secreted protein Shh acts as a crucial factor that patterns the ventral forebrain and is required for the division of the primordial eye field and brain into two discrete halves. Gli2 is one of three vertebrate transcription factors implicated as obligatory mediators of Shh signal transduction. Here, we show that loss-of-function mutations in the human GLI2 gene are associated with a distinctive phenotype (within the HPE spectrum) whose primary features include defective anterior pituitary formation and pan-hypopituitarism, with or without overt forebrain cleavage abnormalities, and HPE-like midfacial hypoplasia. We also demonstrate that these mutations lack GLI2 activity. We report on a functional association between GLI2 and human disease and highlight the role of GLI2 in human head development.

MeSH Terms
Alleles Animals COS Cells DNA Mutational Analysis DNA, Complementary/metabolism Facies Holoprosencephaly/genetics Humans Kruppel-Like Transcription Factors Mice Mice, Inbred C3H Models, Genetic Mutagenesis, Site-Directed Mutation Nuclear Proteins Phenotype Phylogeny Pituitary Gland/abnormalities Prosencephalon/metabolism RNA, Messenger/metabolism Reverse Transcriptase Polymerase Chain Reaction Skin Neoplasms/metabolism Transcription Factors/genetics,metabolism Transfection Xenopus Zinc Finger Protein Gli2
Chemicals
DNA, Complementary GLI2 protein, human Gli2 protein, mouse Kruppel-Like Transcription Factors Nuclear Proteins RNA, Messenger Transcription Factors Zinc Finger Protein Gli2
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Roessler Erich
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1852, USA.
Du Yang-Zhu
Mullor Jose L
Casas Esther
Allen William P
Gillessen-Kaesbach Gabriele
Roeder Elizabeth R
Ming Jeffrey E
Ruiz i Altaba Ariel
Muenke Maximilian
References (42)
42 references, click to expand
  1. Gli2, but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathway.
    Development. 2002 Oct;129(20):4753-61 PMID: 12361967
  2. Hedgehog-Gli signalling and the growth of the brain.
    Nat Rev Neurosci. 2002 Jan;3(1):24-33 PMID: 11823802
  3. Genetic analysis of zebrafish gli1 and gli2 reveals divergent requirements for gli genes in vertebrate development.
    Development. 2003 Apr;130(8):1549-64 PMID: 12620981
  4. How a Hedgehog might see holoprosencephaly.
    Hum Mol Genet. 2003 Apr 1;12 Spec No 1:R15-25 PMID: 12668593
  5. A mouse model of greig cephalopolysyndactyly syndrome: the extra-toesJ mutation contains an intragenic deletion of the Gli3 gene.
    Nat Genet. 1993 Mar;3(3):241-6 PMID: 8387379
  6. Extra-toes (Xt) homozygous mutant mice demonstrate a role for the Gli-3 gene in the development of the forebrain.
    Acta Anat (Basel). 1994;150(1):38-44 PMID: 7976186
  7. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function.
    Nature. 1996 Oct 3;383(6599):407-13 PMID: 8837770
  8. Mutations in the human Sonic Hedgehog gene cause holoprosencephaly.
    Nat Genet. 1996 Nov;14(3):357-60 PMID: 8896572
  9. A binding site for Gli proteins is essential for HNF-3beta floor plate enhancer activity in transgenics and can respond to Shh in vitro.
    Development. 1997 Apr;124(7):1313-22 PMID: 9118802
  10. Proteolysis that is inhibited by hedgehog targets Cubitus interruptus protein to the nucleus and converts it to a repressor.
    Cell. 1997 Jun 27;89(7):1043-53 PMID: 9215627
  11. Gli1 is a target of Sonic hedgehog that induces ventral neural tube development.
    Development. 1997 Jul;124(13):2537-52 PMID: 9216996
  12. Control of cell pattern in the neural tube by the zinc finger transcription factor and oncogene Gli-1.
    Neuron. 1997 Jul;19(1):15-26 PMID: 9247260
  13. Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours.
    Nature. 1997 Oct 23;389(6653):876-81 PMID: 9349822
  14. Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired.
    Nat Genet. 1998 Oct;20(2):180-3 PMID: 9771712
  15. Comparative synteny cloning of zebrafish you-too: mutations in the Hedgehog target gli2 affect ventral forebrain patterning.
    Genes Dev. 1999 Feb 15;13(4):388-93 PMID: 10049354
  16. Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3.
    J Biol Chem. 1999 Mar 19;274(12):8143-52 PMID: 10075717
  17. GLI3 mutations in human disorders mimic Drosophila cubitus interruptus protein functions and localization.
    Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):2880-4 PMID: 10077605
  18. Early steps in pituitary organogenesis.
    Trends Genet. 1999 Jun;15(6):236-40 PMID: 10354584
  19. Gli proteins encode context-dependent positive and negative functions: implications for development and disease.
    Development. 1999 Jun;126(14):3205-16 PMID: 10375510
  20. Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling.
    Development. 1999 Sep;126(17):3915-24 PMID: 10433919
  21. The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; No phenotype prediction from the position of GLI3 mutations.
    Am J Hum Genet. 1999 Sep;65(3):645-55 PMID: 10441570
  22. Cloning of novel isoforms of the human Gli2 oncogene and their activities to enhance tax-dependent transcription of the human T-cell leukemia virus type 1 genome.
    J Virol. 1998 May;72(5):3958-64 PMID: 9557682
  23. Combinatorial Gli gene function in floor plate and neuronal inductions by Sonic hedgehog.
    Development. 1998 Jun;125(12):2203-12 PMID: 9584120
  24. Gli/Zic factors pattern the neural plate by defining domains of cell differentiation.
    Nature. 1998 Jun 11;393(6685):579-83 PMID: 9634234
  25. Diminished Sonic hedgehog signaling and lack of floor plate differentiation in Gli2 mutant mice.
    Development. 1998 Jul;125(14):2533-43 PMID: 9636069
  26. Gli2 is required for induction of floor plate and adjacent cells, but not most ventral neurons in the mouse central nervous system.
    Development. 1998 Aug;125(15):2759-70 PMID: 9655799
  27. The Shh signalling pathway in tooth development: defects in Gli2 and Gli3 mutants.
    Development. 1998 Aug;125(15):2803-11 PMID: 9655803
  28. Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus.
    Nat Genet. 1998 Sep;20(1):54-7 PMID: 9731531
  29. Absence of ventral cell populations in the developing brain in a rat model of the Smith-Lemli-Opitz syndrome.
    Am J Med Genet. 1999 Nov 26;87(3):207-16 PMID: 10564872
  30. Basal cell carcinomas in mice overexpressing Gli2 in skin.
    Nat Genet. 2000 Mar;24(3):216-7 PMID: 10700170
  31. Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation.
    Development. 2000 Apr;127(8):1593-605 PMID: 10725236
  32. Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1.
    Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3438-43 PMID: 10725363
  33. Expression of the vertebrate Gli proteins in Drosophila reveals a distribution of activator and repressor activities.
    Development. 2000 Oct;127(19):4293-301 PMID: 10976059
  34. Gli2 functions in FGF signaling during antero-posterior patterning.
    Development. 2000 Oct;127(20):4395-405 PMID: 11003839
  35. Specification of ventral neuron types is mediated by an antagonistic interaction between Shh and Gli3.
    Nat Neurosci. 2000 Oct;3(10):979-85 PMID: 11017169
  36. Hedgehog signaling is required for pituitary gland development.
    Development. 2001 Feb;128(3):377-86 PMID: 11152636
  37. Physical and functional interactions between Zic and Gli proteins.
    J Biol Chem. 2001 Mar 9;276(10):6889-92 PMID: 11238441
  38. Wnt signals are targets and mediators of Gli function.
    Curr Biol. 2001 May 15;11(10):769-73 PMID: 11378387
  39. Midline and laterality defects: left and right meet in the middle.
    Bioessays. 2001 Oct;23(10):888-900 PMID: 11598956
  40. Gli1 can rescue the in vivo function of Gli2.
    Development. 2001 Dec;128(24):5161-72 PMID: 11748151
  41. The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis.
    Development. 2001 Dec;128(24):5201-12 PMID: 11748155
  42. Dorsoventral patterning is established in the telencephalon of mutants lacking both Gli3 and Hedgehog signaling.
    Development. 2002 Nov;129(21):4963-74 PMID: 12397105
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.2235734100
Published
2003-11-11
Epub
2003-00-27
Pages
13424-9
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC263830
Subset
IM
Grants
NICHD NIH HHS · HD01218 · United States
NICHD NIH HHS · HD29862 · United States
External Links
PubMed source DOI: 10.1073/pnas.2235734100 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2