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Abstract
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-β) 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-β or retinoic acid. Developmental control of proliferation by Tgif may play a role in the pathogenesis of HPE.
Supplemental material for this article may be found at http://mcb.asm.org/.
We thank K. Humphries and P. Rosten for the use of their BAC clone library, E. Robertson for providing the CCE cell line, D. Wotton and J. Massague for human TGIF cDNA, G. Nolan for Phoenix Eco cell lines, R. Grewal for injecting blastocysts, and G. DeJong, L. Laycock, and G. Thornbury for FACS support.
This study was supported by the National Cancer Institute of Canada with funding from the Terry Fox Foundation. P.A.H. is a Michael Smith Foundation for Health Research Scholar and a Canadian Institute of Health Research New Investigator. L.M. acknowledges the Effie I. Lefeaux Scholarship in Mental Retardation and the Albert B. and Mary Steiner award for travel.