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Role of TGIF in cell cycle control and establishment of laterality Mar, Lynn

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 TG-Interacting Factor (TGIF) 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 non-random chromosomal aberrations in HPE patients. TGIF is a transcription factor that contains a three amino acid loop extension (TALE) homeodomain and functions both as a co-repressor of the TGF-β pathway and as a competitor of the retinoic acid pathway. Mice made deficient for Tgif exhibited laterality defects and growth retardation, and developed kinked tails. Analysis of Tgif⁻ʹ⁻ mouse embryonic fibroblasts (MEFs) in vitro demonstrated that Tgif regulates proliferation and progression through the G₁ cell cycle phase. 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.

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