title: 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.
abstract: 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.
authors: Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, United States of America.
authors: Francesca
authors: F
authors: Lugani
authors: Ripla
authors: R
authors: Arora
authors: Natalia
authors: N
authors: Papeta
authors: Ami
authors: A
authors: Patel
authors: Zongyu
authors: Z
authors: Zheng
authors: Roel
authors: R
authors: Sterken
authors: Ruth A
authors: RA
authors: Singer
authors: Gianluca
authors: G
authors: Caridi
authors: Cathy
authors: C
authors: Mendelsohn
authors: Lori
authors: L
authors: Sussel
authors: Virginia E
authors: VE
authors: Papaioannou
authors: Ali G
authors: AG
authors: Gharavi
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006801:Humans; D008648:Mesoderm / Q000002:abnormalities / Q000254:growth & development; D051379:Mice; D016254:Mutagenesis, Insertional / Q000235:genetics*; D010179:Pancreas / Q000002:abnormalities / Q000254:growth & development; D018626:Retroelements / Q000235:genetics*; D013116:Spinal Cord / Q000002:abnormalities / Q000254:growth & development; D013623:Tail / Q000033:anatomy & histology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D018626:Retroelements; D014157:Transcription Factors; C062602:transcription factor PTF1