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Molecular and Cellular Biology, April 2002, p. 2318-2328, Vol. 22, No. 7
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.7.2318-2328.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Targeted Mutagenesis of the Hira Gene Results in Gastrulation Defects and Patterning Abnormalities of Mesoendodermal Derivatives Prior to Early Embryonic Lethality

Catherine Roberts,1 Helen F. Sutherland,1 Hannah Farmer,1,{dagger} Wendy Kimber,2 Stephanie Halford,1,{ddagger} Alisoun Carey,1,§ Joshua M. Brickman,3 Anthony Wynshaw-Boris,4 and Peter J. Scambler1*

Molecular Medicine Unit, Institute of Child Health, London WC1N 1EH,1 Centre for Genome Research, University of Edinburgh, Edinburgh EH9 3JQ United Kingdom,3 National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224,2 Departments of Pediatrics and Medicine, University of California at San Diego School of Medicine, La Jolla, California 92093-06274

Received 30 October 2001/ Returned for modification 26 November 2001/ Accepted 27 December 2001

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.

* Corresponding author. Mailing address: Rm. 211, Molecular Medicine Unit, Institute of Child Health, 30 Guilford St., London WC1N 1EH, United Kingdom. Phone: 44(0)207-905-2635. Fax: 44(0)207-831-0488. E-mail: p.scambler{at}ich.ucl.ac.uk.

{dagger} Present address: Institute for Cancer Research, London SW3 6JB, United Kingdom.

{ddagger} Present address: ICSM, Hammersmith Hospital, London W12 0NN, United Kingdom.

§ Present address: Oxagen, Inc., Abingdon OX14 4RY, United Kingdom.

Molecular and Cellular Biology, April 2002, p. 2318-2328, Vol. 22, No. 7
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.7.2318-2328.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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