Ectopic Expression of Ptf1a Induces Spinal Defects, Urogenital Defects, and Anorectal Malformations in Danforth's Short Tail Mice
Year: 2013
Type: article
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.
Source: PLoS Genetics
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,043
Awards: Analysis of gene-trap mouse lines disrupting long intergenic non-coding RNA genes., Elucidation for molecular etiology of Danforth's short tail (Sd)mutant, a caudal regression model mouse, Genetic studies on unique phenotypes in MSM/Ms mouse strain, Analysis of genome inactivation mechanism using chromosomal site-specific gene integration, G7848117918, Establishment of Cre-driver mouse lines by using the Exchangeable Gene Trap Ckones.
OpenAlex ID: W2053759809