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Molecular and Cellular Biology, June 2006, p. 4302-4310, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.02156-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Embryonic Fibroblasts from Mice Lacking Tgif Were Defective in Cell Cycling{dagger}

Lynn Mar and Pamela A. Hoodless*

Terry Fox Laboratory, BC Cancer Agency and Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

Received 7 November 2005/ Returned for modification 8 December 2005/ Accepted 19 March 2006

Holoprosencephaly (HPE) is the most common structural anomaly of the human brain, resulting from incomplete cleavage of the developing forebrain during embryogenesis. Haploinsufficient mutations in the TG-interacting factor (TGIF) gene were previously identified in a subset of HPE families and sporadic patients, and this gene is located within a region of chromosome 18 that is associated with nonrandom chromosomal aberrations in HPE patients. TGIF is a three-amino-acid loop extension (TALE) homeodomain-containing transcription factor that functions both as a corepressor of the transforming growth factor beta (TGF-ß) pathway and as a competitor of the retinoic acid pathway. Here we describe mice deficient in Tgif that exhibited laterality defects and growth retardation and developed kinked tails. Cellular analysis of mutant mouse embryonic fibroblasts (MEFs) demonstrated for the first time that Tgif regulates proliferation and progression through the G1 cell cycle phase. Additionally, wild-type human TGIF was able to rescue this proliferative defect in MEFs. In contrast, a subset of human Tgif mutations detected in HPE patients was unable to rescue the proliferative defect. However, an absence of Tgif did not alter the normal inhibition of proliferation caused by treatment with TGF-ß or retinoic acid. Developmental control of proliferation by Tgif may play a role in the pathogenesis of HPE.

* Corresponding author. Mailing address: Terry Fox Laboratory, British Columbia Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, Canada, V5Z 1L3. Phone: (604) 675-8133. Fax: (604) 877-0712. E-mail: hoodless{at}bccrc.ca.

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

Molecular and Cellular Biology, June 2006, p. 4302-4310, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.02156-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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