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. 2003 Sep;165(1):299–307. doi: 10.1093/genetics/165.1.299

Undulated short-tail deletion mutation in the mouse ablates Pax1 and leads to ectopic activation of neighboring Nkx2-2 in domains that normally express Pax1.

Chikara Kokubu 1, Bettina Wilm 1, Tomoko Kokubu 1, Matthias Wahl 1, Isabel Rodrigo 1, Norio Sakai 1, Fabio Santagati 1, Yoshihide Hayashizaki 1, Misao Suzuki 1, Ken-Ichi Yamamura 1, Kuniya Abe 1, Kenji Imai 1
PMCID: PMC1462742  PMID: 14504237

Abstract

Previous studies have indicated that the Undulated short-tail deletion mutation in mouse Pax1 (Pax1(Un-s)) not only ablates Pax1, but also disturbs a gene or genes nearby Pax1. However, which gene(s) is involved and how the Pax1(Un-s) phenotype is confined to the Pax1-positive tissues remain unknown. In the present study, we determined the Pax1(Un-s) deletion interval to be 125 kb and characterized genes around Pax1. We show that the Pax1(Un-s) mutation affects four physically linked genes within or near the deletion, including Pax1, Nkx2-2, and their potential antisense genes. Remarkably, Nkx2-2 is ectopically activated in the sclerotome and limb buds of Pax1(Un-s) embryos, both of which normally express Pax1. This result suggests that the Pax1(Un-s) deletion leads to an illegitimate interaction between remotely located Pax1 enhancers and the Nkx2-2 promoter by disrupting an insulation mechanism between Pax1 and Nkx2-2. Furthermore, we show that expression of Bapx1, a downstream target of Pax1, is more strongly affected in Pax1(Un-s) mutants than in Pax1-null mutants, suggesting that the ectopic expression of Nkx2-2 interferes with the Pax1-Bapx1 pathway. Taken together, we propose that a combination of a loss-of-function mutation of Pax1 and a gain-of-function mutation of Nkx2-2 is the molecular basis of the Pax1(Un-s) mutation.

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Selected References

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