Home LiteratureArticle Details
PMID: 11884616 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Targeted mutagenesis of the Hira gene results in gastrulation defects and patterning abnormalities of mesoendodermal derivatives prior to early embryonic lethality.

Molecular and cellular biology ·Vol. 22 ·No. 7 ·2002-04-00 ·Pages 2318-28

Roberts C, Sutherland HF, Farmer H, Kimber W, Halford S, Carey A, Brickman JM, Wynshaw-Boris A, Scambler PJ

Abstract

The Hira gene encodes a nuclear WD40 domain protein homologous to the yeast transcriptional corepressors Hir1p and Hir2p. Using targeted mutagenesis we demonstrate that Hira is essential for murine embryogenesis. Analysis of inbred 129Sv embryos carrying the null mutation revealed an initial requirement during gastrulation, with many mutant embryos having a distorted primitive streak. Mutant embryos recovered at later stages have a range of malformations with axial and paraxial mesendoderm being particularly affected, a finding consistent with the disruption of gastrulation seen earlier in development. This phenotype could be partially rescued by a CD1 genetic background, although the homozygous mutation was always lethal by embryonic day 11, with death probably resulting from abnormal placentation and failure of cardiac morphogenesis.

MeSH Terms
Animals Blotting, Western Body Patterning/genetics Cell Cycle Proteins Congenital Abnormalities/genetics,pathology Embryo Loss/genetics Embryonic and Fetal Development/genetics Gastrula/metabolism,pathology Gene Deletion Genes, Essential/genetics Histone Chaperones Homozygote Immunohistochemistry In Situ Hybridization Mesoderm/metabolism,pathology Mice Mutagenesis, Site-Directed/genetics Nervous System/embryology,metabolism,pathology Nuclear Proteins/deficiency,genetics Phenotype RNA, Messenger/genetics,metabolism Reverse Transcriptase Polymerase Chain Reaction Transcription Factors/deficiency,genetics
Chemicals
Cell Cycle Proteins Hira protein, mouse Histone Chaperones Nuclear Proteins RNA, Messenger Transcription Factors
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Roberts Catherine
Molecular Medicine Unit, Institute of Child Health, London WC1N 1EH, United Kingdom.
Sutherland Helen F
Farmer Hannah
Kimber Wendy
Halford Stephanie
Carey Alisoun
Brickman Joshua M
Wynshaw-Boris Anthony
Scambler Peter J
References (56)
56 references, click to expand
  1. Anterior patterning by synergistic activity of the early gastrula organizer and the anterior germ layer tissues of the mouse embryo.
    Development. 1999 Nov;126(22):5171-9 PMID: 10529433
  2. Seeking a regulatory roadmap for heart morphogenesis.
    Semin Cell Dev Biol. 1999 Feb;10(1):99-107 PMID: 10355034
  3. The morphogenetic role of midline mesendoderm and ectoderm in the development of the forebrain and the midbrain of the mouse embryo.
    Development. 2000 May;127(9):1799-813 PMID: 10751169
  4. Chamber formation and morphogenesis in the developing mammalian heart.
    Dev Biol. 2000 Jul 15;223(2):266-78 PMID: 10882515
  5. The glial cells missing-1 protein is essential for branching morphogenesis in the chorioallantoic placenta.
    Nat Genet. 2000 Jul;25(3):311-4 PMID: 10888880
  6. The 22q11 deletion syndromes.
    Hum Mol Genet. 2000 Oct;9(16):2421-6 PMID: 11005797
  7. DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1.
    Nat Genet. 2001 Mar;27(3):286-91 PMID: 11242110
  8. TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome.
    Cell. 2001 Feb 23;104(4):619-29 PMID: 11239417
  9. HIRA, the human homologue of yeast Hir1p and Hir2p, is a novel cyclin-cdk2 substrate whose expression blocks S-phase progression.
    Mol Cell Biol. 2001 Mar;21(5):1854-65 PMID: 11238922
  10. A role for BMP signalling in heart looping morphogenesis in Xenopus.
    Dev Biol. 2001 Apr 1;232(1):191-203 PMID: 11254357
  11. Subnuclear localization and mitotic phosphorylation of HIRA, the human homologue of Saccharomyces cerevisiae transcriptional regulators Hir1p/Hir2p.
    Biochem J. 2001 Sep 1;358(Pt 2):447-55 PMID: 11513744
  12. Characterization of HIR1 and HIR2, two genes required for regulation of histone gene transcription in Saccharomyces cerevisiae.
    Mol Cell Biol. 1993 Jan;13(1):28-38 PMID: 8417331
  13. A series of vectors that simplify mammalian gene targeting.
    Transgenic Res. 1993 Jul;2(4):238-44 PMID: 8364606
  14. Anterior mesendoderm induces mouse Engrailed genes in explant cultures.
    Development. 1993 May;118(1):139-49 PMID: 8375331
  15. Isolation of a putative transcriptional regulator from the region of 22q11 deleted in DiGeorge syndrome, Shprintzen syndrome and familial congenital heart disease.
    Hum Mol Genet. 1993 Dec;2(12):2099-107 PMID: 8111380
  16. HNF-3 beta is essential for node and notochord formation in mouse development.
    Cell. 1994 Aug 26;78(4):561-74 PMID: 8069909
  17. The winged-helix transcription factor HNF-3 beta is required for notochord development in the mouse embryo.
    Cell. 1994 Aug 26;78(4):575-88 PMID: 8069910
  18. The ancient regulatory-protein family of WD-repeat proteins.
    Nature. 1994 Sep 22;371(6495):297-300 PMID: 8090199
  19. fgfr-1 is required for embryonic growth and mesodermal patterning during mouse gastrulation.
    Genes Dev. 1994 Dec 15;8(24):3032-44 PMID: 8001822
  20. Murine FGFR-1 is required for early postimplantation growth and axial organization.
    Genes Dev. 1994 Dec 15;8(24):3045-57 PMID: 8001823
  21. Requirement for Lim1 in head-organizer function.
    Nature. 1995 Mar 30;374(6521):425-30 PMID: 7700351
  22. twist is required in head mesenchyme for cranial neural tube morphogenesis.
    Genes Dev. 1995 Mar 15;9(6):686-99 PMID: 7729687
  23. A human homolog of the S. cerevisiae HIR1 and HIR2 transcriptional repressors cloned from the DiGeorge syndrome critical region.
    Hum Mol Genet. 1995 May;4(5):791-9 PMID: 7633437
  24. Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse.
    Genes Dev. 1995 Sep 1;9(17):2105-16 PMID: 7657163
  25. A targeted mouse Otx2 mutation leads to severe defects in gastrulation and formation of axial mesoderm and to deletion of rostral brain.
    Development. 1996 Jan;122(1):243-52 PMID: 8565836
  26. Fibroblast growth factor receptor 3 is a negative regulator of bone growth.
    Cell. 1996 Mar 22;84(6):911-21 PMID: 8601314
  27. Relationship between asymmetric nodal expression and the direction of embryonic turning.
    Nature. 1996 May 9;381(6578):155-8 PMID: 8610012
  28. Role of notochord in specification of cardiac left-right orientation in zebrafish and Xenopus.
    Dev Biol. 1996 Jul 10;177(1):96-103 PMID: 8660880
  29. Hir1p and Hir2p function as transcriptional corepressors to regulate histone gene transcription in the Saccharomyces cerevisiae cell cycle.
    Mol Cell Biol. 1997 Feb;17(2):545-52 PMID: 9001207
  30. Cloning and developmental expression analysis of chick Hira (Chira), a candidate gene for DiGeorge syndrome.
    Hum Mol Genet. 1997 Feb;6(2):237-45 PMID: 9063744
  31. The murine homologue of HIRA, a DiGeorge syndrome candidate gene, is expressed in embryonic structures affected in human CATCH22 patients.
    Hum Mol Genet. 1997 Feb;6(2):247-58 PMID: 9063745
  32. The SIL gene is required for mouse embryonic axial development and left-right specification.
    Nature. 1999 Jun 17;399(6737):691-4 PMID: 10385121
  33. Differences in left-right axis pathways in mouse and chick: functions of FGF8 and SHH.
    Science. 1999 Jul 16;285(5426):403-6 PMID: 10411502
  34. Targeted disruption of Fgf8 causes failure of cell migration in the gastrulating mouse embryo.
    Genes Dev. 1999 Jul 15;13(14):1834-46 PMID: 10421635
  35. A role for transcriptional repressors in targeting the yeast Swi/Snf complex.
    Mol Cell. 1999 Jul;4(1):75-83 PMID: 10445029
  36. Congenital heart disease in mice deficient for the DiGeorge syndrome region.
    Nature. 1999 Sep 23;401(6751):379-83 PMID: 10517636
  37. The orderly allocation of mesodermal cells to the extraembryonic structures and the anteroposterior axis during gastrulation of the mouse embryo.
    Development. 1999 Nov;126(21):4691-701 PMID: 10518487
  38. Left-right asymmetry of a nodal-related gene is regulated by dorsoanterior midline structures during Xenopus development.
    Development. 1997 Apr;124(8):1465-72 PMID: 9108363
  39. Development of sidedness of asymmetric body structures in vertebrates.
    Int J Dev Biol. 1997 Apr;41(2):153-86 PMID: 9184324
  40. Chimeric analysis of fibroblast growth factor receptor-1 (Fgfr1) function: a role for FGFR1 in morphogenetic movement through the primitive streak.
    Development. 1997 Jul;124(14):2829-41 PMID: 9226454
  41. No turning, a mouse mutation causing left-right and axial patterning defects.
    Dev Biol. 1998 Jan 1;193(1):77-89 PMID: 9466889
  42. Chordin regulates primitive streak development and the stability of induced neural cells, but is not sufficient for neural induction in the chick embryo.
    Development. 1998 Feb;125(3):507-19 PMID: 9425145
  43. Smad2 signaling in extraembryonic tissues determines anterior-posterior polarity of the early mouse embryo.
    Cell. 1998 Mar 20;92(6):797-808 PMID: 9529255
  44. Isolation and genomic characterization of the TUPLE1/HIRA gene of the pufferfish Fugu rubripes.
    Gene. 1998 Feb 27;208(2):279-83 PMID: 9524281
  45. Lineage and functional analyses of the mouse organizer.
    Cold Spring Harb Symp Quant Biol. 1997;62:135-44 PMID: 9598345
  46. Hir proteins are required for position-dependent gene silencing in Saccharomyces cerevisiae in the absence of chromatin assembly factor I.
    Mol Cell Biol. 1998 Aug;18(8):4793-806 PMID: 9671489
  47. The transcription factor HNF3beta is required in visceral endoderm for normal primitive streak morphogenesis.
    Development. 1998 Aug;125(16):3015-25 PMID: 9671576
  48. cyclops encodes a nodal-related factor involved in midline signaling.
    Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9932-7 PMID: 9707578
  49. Core histones and HIRIP3, a novel histone-binding protein, directly interact with WD repeat protein HIRA.
    Mol Cell Biol. 1998 Sep;18(9):5546-56 PMID: 9710638
  50. Cloning, chromosome mapping and expression analysis of the HIRA gene from Drosophila melanogaster.
    Biochem Biophys Res Commun. 1998 Aug 19;249(2):486-91 PMID: 9712723
  51. HIRA, a mammalian homologue of Saccharomyces cerevisiae transcriptional co-repressors, interacts with Pax3.
    Nat Genet. 1998 Sep;20(1):74-7 PMID: 9731536
  52. Induction of the zebrafish ventral brain and floorplate requires cyclops/nodal signalling.
    Nature. 1998 Sep 10;395(6698):185-9 PMID: 9744278
  53. Axis development and early asymmetry in mammals.
    Cell. 1999 Jan 22;96(2):195-209 PMID: 9988215
  54. Bmp4 is required for the generation of primordial germ cells in the mouse embryo.
    Genes Dev. 1999 Feb 15;13(4):424-36 PMID: 10049358
  55. The role of the brachyury gene in heart development and left-right specification in the mouse.
    Mech Dev. 1998 Dec;79(1-2):29-37 PMID: 10349618
  56. The organizer factors Chordin and Noggin are required for mouse forebrain development.
    Nature. 2000 Feb 10;403(6770):658-61 PMID: 10688202
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.22.7.2318-2328.2002
Published
2002-04-00
Pages
2318-28
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC133693
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.22.7.2318-2328.2002 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: [email protected]

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