| First Author | Kokubu C | Year | 2003 |
| Journal | Genetics | Volume | 165 |
| Issue | 1 | Pages | 299-307 |
| PubMed ID | 14504237 | Mgi Jnum | J:85847 |
| Mgi Id | MGI:2677127 | Doi | 10.1093/genetics/165.1.299 |
| Citation | Kokubu C, et al. (2003) 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. Genetics 165(1):299-307 |
| abstractText | 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. |
