Tgif1 and Tgif2 Repress Expression of the RabGAP Evi5l

ABSTRACT

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.

KEYWORDS:

• Evi5l
• Tgif
• Tgif1
• Tgif2
• cilium
• regulation of gene expression
• transcription factors

View publisher note:

Articles of Significant Interest Selected from This Issue by the Editors

Supplemental material for this article may be found at https://doi.org/10.1128/MCB.00527-16.

ACKNOWLEDGMENTS

We thank the UVA Advanced Microscopy Facility for technical assistance and members of the Wotton laboratory for helpful discussions.

We declare that we have no conflict of interest.