当社独自技術の可変型トラップ法技術を用いた研究成果が「PLOS GENETICS」に掲載されました。

この度掲載されました論文は、熊本大学生命資源研究・支援センター疾患モデル分野山村教授らの研究グループの成果で、当社独自技術である可変型遺伝子トラップ法を応用した「可変型相同組換え法」を用いて３つのトランスジェニックマウス、８つのノックアウト・ノックインマウス系統を作製し、これらマウスを包括的に解析することにより、重篤な脊椎欠損を示すDanforth's short tail (Sd) マウスの原因を発見した報告です。本報告は、Sdマウスが脊椎欠損、鎖肛、腎臓欠損を呈するヒト尾部退行症候群のモデルマウスであることから、本ヒト疾患の病因の解明につながるものと期待されます。Ectopic Expression of Ptf1a Induces Spinal Defects,Urogenital Defects, and Anorectal Malformations in Danforth's Short Tail Mice Kei Semba, Kimi Araki, Ken-ichirou Matsumoto, Hiroko Suda, Takashi Ando, Akira Sei, Hiroshi Mizuta, Katsumasa Takagi, Mai Nakahara, Mayumi Muta, Gen Yamada, Naomi Nakagata, Aritoshi Iida, Shiro Ikegawa, Yusuke Nakamura, Masatake Araki, Kuniya Abe, Ken-ichi YamamuraAbstract Danforth's short tail (Sd) is a semidominant mutation on mouse chromosome 2, characterized by spinal defects, urogenital defects, and anorectal malformations. However, the gene responsible for the Sd phenotype was unknown. In this study, we identified the molecular basis of the Sd mutation. By positional cloning, we identified the insertion of an early transposon in the Sd candidate locus approximately 12-kb upstream of Ptf1a. We found that insertion of the transposon caused overexpression of three neighboring genes, Gm13344, Gm13336, and Ptf1a, in Sd mutant embryos and that the Sd phenotype was not caused by disruption of an as-yet-unknown gene in the candidate locus. Using multiple knockout and knock-in mouse models, we demonstrated that misexpression of Ptf1a, but not of Gm13344 or Gm13336, in the notochord, hindgut, cloaca, and mesonephros was sufficient to replicate the Sd phenotype. The ectopic expression of Ptf1a in the caudal embryo resulted in attenuated expression of Cdx2 and its downstream target genes T, Wnt3a, and Cyp26a1; we conclude that this is the molecular basis of the Sd phenotype. Analysis of Sd mutant mice will provide insight into the development of the spinal column, anus, and kidney.