期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 37, 期 5, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00527-16
关键词
Evi5l; Tgif; Tgif1; Tgif2; cilium; regulation of gene expression; transcription factors
资金
- NCI NIH HHS [T32 CA009109, P30 CA044579] Funding Source: Medline
- NCRR NIH HHS [S10 RR025616] Funding Source: Medline
- NICHD NIH HHS [R01 HD034807] Funding Source: Medline
- NIGMS NIH HHS [T32 GM008136, R01 GM099853] Funding Source: Medline
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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