Dataset Information

Tgif1 and Tgif2 Regulate Axial Patterning in Mouse.

ABSTRACT: Tgif1 and Tgif2 are transcriptional repressors that inhibit the transcriptional response to transforming growth factor ? signaling, and can repress gene expression by direct binding to DNA. Loss of function mutations in TGIF1 are associated with holoprosencephaly (HPE) in humans. In mice, embryos lacking both Tgif1 and Tgif2 fail to complete gastrulation, and conditional double null embryos that survive past gastrulation have HPE and do not survive past mid-gestation. Here we show that in mice of a relatively pure C57BL/6 strain background, loss of Tgif1 alone results in defective axial patterning and altered expression of Hoxc6. The primary defects in Tgif1 null embryos are the presence of extra ribs on the C7 vertebra, consistent with a posterior transformation phenotype. In addition we observed defective cervical vertebrae, primarily C1-C5, in both adult mice and embryos that lacked Tgif1. The combination of Tgif1 and Tgif2 mutations increases the severity and penetrance of the posterior transformation phenotype, without altering the type of defects seen. Similarly, exposure of Tgif1 mutant embryos to retinoic acid at E8.5 increased the severity and penetrance of the Tgif1 phenotype. This suggests that Tgif1 and Tgif2 regulate axial patterning and that reduced TGIF function sensitizes embryos to the effects of retinoic acid.

SUBMITTER: Melhuish TA

PROVIDER: S-EPMC4871493 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Tgif1 and Tgif2 Regulate Axial Patterning in Mouse.

Melhuish Tiffany A TA Taniguchi Kenichiro K Wotton David D

PloS one 20160517 5

Tgif1 and Tgif2 are transcriptional repressors that inhibit the transcriptional response to transforming growth factor β signaling, and can repress gene expression by direct binding to DNA. Loss of function mutations in TGIF1 are associated with holoprosencephaly (HPE) in humans. In mice, embryos lacking both Tgif1 and Tgif2 fail to complete gastrulation, and conditional double null embryos that survive past gastrulation have HPE and do not survive past mid-gestation. Here we show that in mice o ...[more]

PMID: 27187787

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Project description:Normal, chimeric-transgenic, and transgenic mice have been used to study the axial patterns of ileal lipid-binding protein gene (Ilbp) expression during and after completion of gut morphogenesis. Ilbp is initially activated in enterocytes in bidirectional wave that expands proximally in the ileum and distally to the colon during late gestation and the first postnatal week. This activation occurs at the same time that a wave of cytodifferentiation of the gut endoderm is completing its unidirectional journey from duodenum to colon. The subsequent contraction of Ilbp's expression domain, followed by its reexpansion from the distal to proximal ileum, coincides with a critical period in gut morphogenesis (postnatal days 7-28) when its proliferative units (crypts) form, establish their final stem cell hierarchy, and then multiply through fission. The wave of reactivation is characterized by changing patterns of Ilbp expression: (a) at the proximal most boundary of the wave, villi contain a mixed population of scattered ileal lipid-binding protein (ILBP)-positive and ILBP-negative enterocytes derived from the same monoclonal crypt; (b) somewhat more distally, villi contain vertical coherent stripes of wholly ILBP-positive enterocytes derived from monoclonal crypts and adjacent, wholly ILBP-negative stripes of enterocytes emanating from other monoclonal crypts; and (c) more distally, all the enterocytes on a villus support Ilbp expression. Functional mapping studies of Ilbp's promoter in transgenic mice indicate that nucleotides -145 to +48 contain cis-acting elements sufficient to produce an appropriately directed distal-to-proximal wave of Ilbp activation in the ileum, to maintain an appropriate axial distribution of monophenotypic wholly reporter-positive villi in the distal portion of the ileum, as well as striped and speckled villi in the proximal portion of its expression domain, and to correctly support reporter production in villus-associated ileal enterocytes. Nucleotides -417 to -146 of Ilbp contain a "temporal" suppressor that delays initial ileal activation of the gene until the second postnatal week. Nucleotides -913 to -418 contain a temporal suppressor that further delays initial activation of the gene until the third to fourth postnatal week, a spatial suppressor that prohibits gene expression in the proximal quarter of the ileum and in the proximal colon, and a cell lineage suppressor that prohibits expression in goblet cells during the first two postnatal weeks.

Dataset Information

Tgif1 and Tgif2 Regulate Axial Patterning in Mouse.

Publications

Tgif1 and Tgif2 Regulate Axial Patterning in Mouse.

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