Tgif and Smad2 mutations increase mammalian sensitivity to retinoic acid teratogenesis
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Date
2005-06
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The Ohio State University
Abstract
Mouse model systems have proven very useful in the study of human birth defects. Such is the case for holoprosencephaly (HPE), which results from improper division of the forebrain. One gene that has been associated with human cases of HPE is TG-interacting factor (TGIF). This gene was first discovered through its ability to bind retinoid X receptor response elements and repress retinoid X receptor-alpha mediated transcription. Breeding mice possessing a targeted null allele of Tgif reveals that Tgif mutations alone do not result in HPE. Instead, Tgif mutations may be required in conjunction with other genetic mutations or environmental factors in order to cause HPE. Previous studies showing that prenatal exposure to retinoic acid (RA) results in HPE sparked interest in the function of Tgif in RA signaling. Teratogenesis experiments demonstrate that Tgif mutations result in an increased susceptibility to HPE development through overexposure to all-trans retinoic acid (ATRA). These results represent a novel cooperation between environmental and genetic factors in the etiology of HPE. Because Tgif has also been implicated in transforming growth factor beta (TGF-β) signaling, similar teratogenesis experiments were performed with mice harboring null mutations in Smad2, a TGF-β signal transducer that physically interacts with Tgif. Heterozygous loss of Smad2 also results in a predisposition to developing HPE through ATRA teratogenesis. Analyses using a retinoid responsive lacZ reporter gene provide evidence that embryonic day 9.5 and 10.5 embryos with Tgif or Smad2 mutations maintain an increased level of RA signaling in the forebrain. These observations support Tgif as a mediator of RA signaling during development and imply a novel interaction between RA and TGF-β signaling.
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Keywords
holoprosencephaly, HPE, all-trans retinoic acid, ATRA, smad3, TG-interacting factor