Elucidation for molecular etiology of Danforth's short tail (Sd)mutant, a caudal regression model mouse

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Caudal regression syndrome (CRS) is a congenital heterogeneousconstellation of caudal anomalies that includes varying degrees of agenesis of the spinalcolumn, anorectal malformations, and genitourinary anomalies(Ando T., Semba K. et al.Mech Dev. 128:129-40. 2011.). Its pathogenesis is unclear. However, it could be the resultof excessive physiologic regression of the embryonic caudal region based on analyses ofthe various mouse mutants carrying caudal agenesis. Among the mouse mutants, theDanforth’s short tail (Sd) mouse is considered a best model for human CRS. Sd is asemidominant mutation, characterized by spinal defects, urogenital defects, andanorectal malformations, thus showing phenotypic similarity to human CRS. Although Sdis known to map to mouse chromosome 2, little is known about the molecular nature of Sd.Here, we demonstrate an insertion of one type of retrotransposon near the Ptf1a gene.This resulted in ectopic expression of Ptf1a gene in the caudal region of the embryo anddownregulation of Cdx2 and its downstream targets, leading to characteristic phenotypesin Sd mouse. Thus, Sd mutant mice will provide insight into the development of the spinalcolumn, anus and kidney(Semba K. et al. PLoS Genet. 9:e1003204. 2013.).