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

• DOI: 10.1371/journal.pgen.1003206
• Publication Date: 2013-02-21T23:37:44Z
• Authors: Francesca Lugani; Ripla Arora; Natalia Papeta; Ami Patel; Zongyu Zheng; Roel Sterken; Ruth A. Singer; Gianluca Caridi; Cathy Mendelsohn; Lori Sussel; Virginia E. Papai...; Ali G. Gharavi
• Keywords: Ectopic expression; Haploinsufficiency; Notochord; Lateral plate mesoderm

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