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Previous studies have indicated that the Undulated short-tail deletion mutation in mouse Pax1 (Pax1Un-s) not only ablates Pax1, but also disturbs a gene or genes nearby Pax1. However, which gene(s) is involved and how the Pax1Un-s phenotype is confined to the Pax1-positive tissues remain unknown. In the present study, we determined the Pax1Un-s deletion interval to be 125 kb and characterized genes around Pax1. We show that the Pax1Un-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 Pax1Un-s embryos, both of which normally express Pax1. This result suggests that the Pax1Un-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 Pax1Un-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 Pax1Un-s mutation.

genetics

Undulated short-tailDeletion Mutation in the Mouse AblatesPax1and Leads to Ectopic Activation of NeighboringNkx2-2in Domains That Normally ExpressPax1