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Molecular and Cellular Biology, May 2005, p. 3639-3647, Vol. 25, No. 9
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.9.3639-3647.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Targeted Disruption of Tgif, the Mouse Ortholog of a Human Holoprosencephaly Gene, Does Not Result in Holoprosencephaly in Mice{dagger}

Jun Shen and Christopher A. Walsh*

Howard Hughes Medical Institute, Department of Neurology, Beth Israel Deaconess Medical Center, and Program in Neuroscience, Division of Medical Sciences, Graduate School of Arts and Sciences, Harvard University, Boston, Massachusetts 02115

Received 8 January 2005/ Accepted 5 February 2005

5'-TG-3'-interacting factor or transforming growth factor beta (TGF-ß)-induced factor (TGIF) belongs to a family of evolutionarily conserved proteins that are characterized by an atypical three-amino-acid loop extension homeodomain. In vitro studies have implicated TGIF as a transcriptional repressor and corepressor in retinoid and TGF-ß signaling pathways that regulate several important biological processes. Heterozygous nonsense and missense mutations of the human TGIF gene have been associated with holoprosencephaly, the most common congenital malformation of the forebrain. In mice, Tgif mRNA is expressed ubiquitously in the ventricular neuroepithelium at embryonic day 10.5 (E10.5) but displays a medial to lateral gradient in the developing cerebral cortex at E12.5. The expression quickly declines by E14.5. The spatiotemporal expression profile of Tgif is consistent with its involvement in midline forebrain development. To better understand the function of Tgif in forebrain patterning and proliferation in vivo, we generated mice lacking Tgif by targeted deletion of exons 2 and 3, which encode 98% of the amino acids. Tgif–/– mice had no detectable Tgif protein by Western blotting. Surprisingly, however, these mice were viable and fertile. In addition, there were no discernible derangements in any of the major organ systems, including the forebrain. Overall our results point to a possible functional redundancy of Tgif, potentially provided by the closely related Tgif2.

* Corresponding author. Mailing address: Howard Hughes Medical Institute, Department of Neurology, Beth Israel Deaconess Medical Center, NRB 266, 77 Avenue Louis Pasteur, Boston, MA 02115. Phone: (617) 667-0813. Fax: (617) 667-0815. E-mail: cwalsh{at}bidmc.harvard.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, May 2005, p. 3639-3647, Vol. 25, No. 9
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.9.3639-3647.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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