Expression and functional analysis of <i>Tgif</i> during mouse midline development

Jin, Jiu-Zhen; Gu, Shi; McKinney, Patrick; Ding, Jixiang

doi:10.1002/dvdy.20642

Cited by 31 publications

(37 citation statements)

References 33 publications

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“…Tgif Ϫ/Ϫ mice did not develop HPE and were viable. Similar observations were also made recently by others (4,20,45). This distinction between humans and mice may reflect the importance of genetic modifiers in HPE (36).…”

Section: Discussionsupporting

confidence: 88%

Embryonic Fibroblasts from Mice Lacking Tgif Were Defective in Cell Cycling

Mar

Hoodless

2006

Molecular and Cellular Biology

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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-␤) 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 G 1 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-␤ or retinoic acid. Developmental control of proliferation by Tgif may play a role in the pathogenesis of HPE.

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Section: Discussionsupporting

confidence: 88%

Embryonic Fibroblasts from Mice Lacking Tgif Were Defective in Cell Cycling

Mar

Hoodless

2006

Molecular and Cellular Biology

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“…However, it is not known how loss-of-function mutations in human TGIF1 cause HPE, and in a mixed strain background, targeted mutations in mice have not revealed a clear role for Tgif1 during embryogenesis (Bartholin et al, 2006;Jin et al, 2006;Mar and Hoodless, 2006;Shen and Walsh, 2005). On a more pure C57BL/6J background a proportion of Tgif1 null animals die perinatally, but we have not observed HPE in these mice (Bartholin et al, 2008).…”

Section: Introductionmentioning

confidence: 58%

“…Tgif2 interacts with the mSin3/HDAC complex to repress transcription, and can interact with TGFb-activated Smads, suggesting conserved function (Melhuish et al, 2001;Melhuish and Wotton, 2006). Tgif1 is expressed at high levels throughout the epiblast from 6.0 dpc, and at a lower level in extra-embryonic endoderm and ectoderm (Jin et al, 2006). Tgif2 is expressed throughout the embryo and extraembryonic tissue from 6.0 dpc onwards, consistent with the possibility of overlapping function.…”

Section: Research Articlementioning

confidence: 66%

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Tgif1 and Tgif2 regulate Nodal signaling and are required for gastrulation

et al. 2010

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SUMMARYTgif1 and Tgif2 are transcriptional co-repressors that limit the response to TGFb signaling and play a role in regulating retinoic-acidmediated gene expression. Mutations in human TGIF1 are associated with holoprosencephaly, but it is unclear whether this is a result of deregulation of TGFb/Nodal signaling, or of effects on other pathways. Surprisingly, mutation of Tgif1 in mice results in only relatively mild developmental phenotypes in most strain backgrounds. Here, we show that loss-of-function mutations in both Tgif1 and Tgif2 result in a failure of gastrulation. By conditionally deleting Tgif1 in the epiblast, we demonstrate that a single wildtype allele of Tgif1 in the extra-embryonic tissue allows the double null embryos to gastrulate and begin organogenesis, suggesting that extra-embryonic Tgif function is required for patterning the epiblast. Genetically reducing the dose of Nodal in embryos lacking all Tgif function results in partial rescue of the gastrulation defects. Conditional double null embryos have defects in leftright asymmetry, which are also alleviated by reducing the dose of Nodal. Together, these data show that Tgif function is required for gastrulation, and provide the first clear evidence that Tgifs limit the transcriptional response to Nodal signaling during early embryogenesis.

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“…Although these human TGIF1 mutations are heterozygous, deletion of Tgif1 in mice had relatively mild phenotypes even as a homozygous mutation (15,(23)(24)(25). However, deletion of both Tgif1 and Tgif2 resulted in gastrulation defects and altered Nodal responses, consistent with a role for Tgifs in TGF-␤ family signaling (26).…”

mentioning

confidence: 85%

Tgif1 and Tgif2 Repress Expression of the RabGAP Evi5l

Anderson

Taniguchi

Hao

et al. 2017

Molecular and Cellular Biology

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Mouse embryos conditionally lacking Tgif1 and Tgif2 have holoprosencephaly and defects in left-right asymmetry. To identify pathways affected by loss of Tgif function during embryogenesis, we performed transcriptome profiling on whole mouse embryos. Among the genes with altered expression in embryos lacking Tgifs were a number with links to cilium function. One of these, Evi5l, encodes a RabGAP that is known to block the formation of cilia when overexpressed. Evi5l expression is increased in Tgif1; Tgif2-null embryos and in double-null mouse embryo fibroblasts (MEFs). Knockdown of Tgifs in a human retinal pigment epithelial cell line also increased EVI5L expression. We show that TGIF1 binds to a conserved consensus TGIF site 5= of the human and mouse Evi5l genes and represses Evi5l expression. In primary MEFs lacking both Tgifs, the number of cells with primary cilia was significantly decreased, and we observed a reduction in the transcriptional response to Shh pathway activation. Reducing Evi5l expression in MEFs lacking Tgifs resulted in a partial restoration of cilium numbers and in the transcriptional response to activation of the Shh pathway. In summary, this work shows that Tgifs regulate ciliogenesis and suggests that Evi5l mediates at least part of this effect.

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Expression and functional analysis of Tgif during mouse midline development

Cited by 31 publications

References 33 publications

Embryonic Fibroblasts from Mice Lacking Tgif Were Defective in Cell Cycling

Embryonic Fibroblasts from Mice Lacking Tgif Were Defective in Cell Cycling

Tgif1 and Tgif2 regulate Nodal signaling and are required for gastrulation

Tgif1 and Tgif2 Repress Expression of the RabGAP Evi5l

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