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.
Highlights
Danforth’s short tail (Sd) is a semidominant spontaneous mutant mouse characterized by severe spinal defects, urogenital defects, and anorectal malformations [1,2,3]
Sd is known to map to mouse chromosome 2, little is known about the molecular nature of the mutation
It could be the result of excessive physiologic regression of the embryonic caudal region based on analyses of the various mouse mutants carrying caudal agenesis
Summary
Danforth’s short tail (Sd) is a semidominant spontaneous mutant mouse characterized by severe spinal defects, urogenital defects, and anorectal malformations [1,2,3]. Heterozygous and homozygous Sd animals display a broad range of abnormalities in the vertebral column, including reduction or absence of the dens axis, reduction of all vertebral bodies in the dorsoventral axis, split vertebrae, and truncation of the caudal vertebral column [4,5,6]. The vertebral columns of Sd/Sd and Sd/+ mice are usually truncated at the seventh thoracic and the sixth caudal vertebral body, respectively [7]. The urogenital system in Sd heterozygotes may display malformations ranging from displaced to missing kidneys. Homozygotes invariably have missing or severely malformed and dislocated kidneys. Homozygous animals die within 24 h after birth [4]
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