Developmental Cell
Volume 43, Issue 3, 6 November 2017, Pages 359-371.e6
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Short Article
Genetic Intersection of Tsix and Hedgehog Signaling during the Initiation of X-Chromosome Inactivation

https://doi.org/10.1016/j.devcel.2017.09.027Get rights and content
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Highlights

  • Hedgehog-GLI signaling regulates X inactivation by potentiating Tsix expression

  • Indian Hedgehog (IHH) contributes to coordination of X-inactivation timing

  • Ihh-null embryos show midgestation female-specific lethality

  • Female-specific Ihh lethality is overcome by a second-site mutation in Tsix

Summary

X-chromosome inactivation (XCI) silences one X chromosome in the female mammal and is essential to peri-implantation development. XCI is thought to be cell autonomous, with all factors required being produced within each cell. Nevertheless, external cues may exist. Here, we search for such developmental signals by combining bioinformatic, biochemical, and genetic approaches. Using ex vivo and in vivo models, we identify the Hedgehog (HH) paracrine system as a candidate signaling cascade. HH signaling keeps XCI in check in pluripotent cells and is transduced by GLI transcription factors to binding sites in Tsix, the antisense repressor of XCI. GLI potentiates Tsix expression and impedes XCI. In vivo, mutating Indian Hedgehog results in a sex ratio bias against females, and the female lethality is rescued by a second-site mutation in Tsix. These data demonstrate a genetic and functional intersection between HH and XCI and support a role for intercellular signaling during XCI.

Keywords

X-chromosome inactivation
Tsix
Xist
embryonic stem cells
second-site mutation
noncoding RNA
cell differentiation
transcription factors

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