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

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^a, Bettina Wilm^a, Tomoko Kokubu^a, Matthias Wahl^a, Isabel Rodrigo^a, Norio Sakai^a, Fabio Santagati^a, Yoshihide Hayashizaki^b, Misao Suzuki^c, Ken-ichi Yamamura^d, Kuniya Abe^e, and Kenji Imai^a
^a GSF-National Research Center for Environment and Health, Institute of Developmental Genetics, 85764 Neuherberg, Germany,
^b RIKEN Genomic Sciences Center, RIKEN Yokohama Institute, Yokohama 230-0045, Japan,
^c Center for Animal Resources and Development, Kumamoto University School of Medicine, 862-0976 Kumamoto, Japan
^d Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, 862-0976 Kumamoto, Japan
^e Technology and Development Team for Mammalian Cellular Dynamics, RIKEN Tsukuba Institute, BioResource Center, Ibaraki 305-0074, Japan

Corresponding author: Kenji Imai, Institute of Developmental Genetics, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany., imai{at}gsf.de (E-mail)

Communicating editor: C. KOZAK

Previous studies have indicated that the Undulated short-taildeletion mutation in mouse Pax1 (Pax1^Un-s) not only ablatesPax1, but also disturbs a gene or genes nearby Pax1. However,which gene(s) is involved and how the Pax1^Un-s phenotype isconfined to the Pax1-positive tissues remain unknown. In thepresent study, we determined the Pax1^Un-s deletion intervalto be 125 kb and characterized genes around Pax1. We show thatthe Pax1^Un-s mutation affects four physically linked genes withinor near the deletion, including Pax1, Nkx2-2, and their potentialantisense genes. Remarkably, Nkx2-2 is ectopically activatedin the sclerotome and limb buds of Pax1^Un-s embryos, both ofwhich normally express Pax1. This result suggests that the Pax1^Un-sdeletion leads to an illegitimate interaction between remotelylocated Pax1 enhancers and the Nkx2-2 promoter by disruptingan 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-nullmutants, suggesting that the ectopic expression of Nkx2-2 interfereswith the Pax1-Bapx1 pathway. Taken together, we propose thata combination of a loss-of-function mutation of Pax1 and a gain-of-functionmutation of Nkx2-2 is the molecular basis of the Pax1^Un-s mutation.

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