title: Ectopic expression of Ptf1a induces spinal defects, urogenital defects, and anorectal malformations in Danforth's short tail mice.
abstract: 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.
authors: Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan.
authors: Kei
authors: K
authors: Semba
authors: Kimi
authors: K
authors: Araki
authors: Ken-ichirou
authors: K
authors: Matsumoto
authors: Hiroko
authors: H
authors: Suda
authors: Takashi
authors: T
authors: Ando
authors: Akira
authors: A
authors: Sei
authors: Hiroshi
authors: H
authors: Mizuta
authors: Katsumasa
authors: K
authors: Takagi
authors: Mai
authors: M
authors: Nakahara
authors: Mayumi
authors: M
authors: Muta
authors: Gen
authors: G
authors: Yamada
authors: Naomi
authors: N
authors: Nakagata
authors: Aritoshi
authors: A
authors: Iida
authors: Shiro
authors: S
authors: Ikegawa
authors: Yusuke
authors: Y
authors: Nakamura
authors: Masatake
authors: M
authors: Araki
authors: Kuniya
authors: K
authors: Abe
authors: Ken-ichi
authors: K
authors: Yamamura
mesh_terms: D001003:Anal Canal / Q000002:abnormalities / Q000254:growth & development; D000818:Animals; D000071616:CDX2 Transcription Factor; D004251:DNA Transposable Elements / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000002:abnormalities / Q000254:growth & development; D051379:Mice; D016254:Mutagenesis, Insertional / Q000235:genetics; D010641:Phenotype; D013131:Spine / Q000002:abnormalities / Q000254:growth & development; D013623:Tail / Q000033:anatomy & histology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000071616:CDX2 Transcription Factor; C487514:Cdx2 protein, mouse; D004251:DNA Transposable Elements; D018398:Homeodomain Proteins; D014157:Transcription Factors; C062602:transcription factor PTF1