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Danforth's short tail mutant ( Sd ) mouse, first described in 1930, is a classic spontaneous mutant exhibiting defects of the axial skeleton, hindgut, and urogenital system. We used meiotic mapping in 1,497 segregants to localize the mutation to a 42.8-kb intergenic segment on chromosome 2. Resequencing of this region identified an 8.5-kb early retrotransposon (ETn) insertion within the highly conserved regulatory sequences upstream of  Pancreas Specific Transcription Factor, 1a  ( Ptf1a ). This mutation resulted in up to tenfold increased expression of  Ptf1a  as compared to wild-type embryos at E9.5 but no detectable changes in the expression levels of other neighboring genes. At E9.5,  Sd  mutants exhibit ectopic  Ptf1a  expression in embryonic progenitors of every organ that will manifest a developmental defect: the notochord, the hindgut, and the mesonephric ducts. Moreover, at E 8.5,  Sd  mutant mice exhibit ectopic  Ptf1a  expression in the lateral plate mesoderm, tail bud mesenchyme, and in the notochord, preceding the onset of visible defects such as notochord degeneration. The  Sd  heterozygote phenotype was not ameliorated by  Ptf1a  haploinsufficiency, further suggesting that the developmental defects result from ectopic expression of  Ptf1a . These data identify disruption of the spatio-temporal pattern of  Ptf1a  expression as the unifying mechanism underlying the multiple congenital defects in Danforth's short tail mouse. This striking example of an enhancer mutation resulting in profound developmental defects suggests that disruption of conserved regulatory elements may also contribute to human malformation syndromes.

plos genetics

A Retrotransposon Insertion in the 5′ Regulatory Domain of Ptf1a Results in Ectopic Gene Expression and Multiple Congenital Defects in Danforth's Short Tail Mouse