Title
Danforth’s short tail ( Sd ) mutant mice, a model of caudal regression syndrome (CRS).

Kei Semba

Abstract:
Caudal regression syndrome (CRS) is a congenital heterogeneous constellation of caudal anomalies that include varying degrees of agenesis of the spinal column, ARMs, genitourinary anomalies, and pulmonary hypoplasia. Its embryogenesis is unclear, but it could be the result of an excess of the physiologic regression of the embryonic tail. Among several mouse mutants that show hypodevelopment of the A-P axis, the Danforth’s short tail ( Sd ) mouse is considered a model for human CRS based on phenotypic similarity in spine, hindgut, and urogenital system . However, the molecular basis of the Sd mutation is unknown. W e identified the nature of Sdmutation . We found an insertion of an early transposon (ETn) in upstream of the Ptf1a gene in Sd.Then, we showed that the insertion of ETn into wild-type allele reproduced the Sd phenotypes, and that the creation of null allele for Ptf1a in the presence of ETn resulted in disappearance ofSd phenotypes . We further established a mouse line, E Tn- AK/Ptf1a Ptf1a , by returning Ptf1acDNA into this locus by Cre mediated gene replacement. The restoration of Ptf1a expression in E Tn- AK/Ptf1a Ptf1a mice reproduced similar phenotypes as in Sd . Interestingly, ETn insertion caused the ectopic expression of Ptf1a and resultant attenuated expression of Cdx2 , T , Wnt3a , and Cyp26a1 in the notochord, hindgut, cloaca and mesonephros where Sd phenotypes were observed. The suppressed expression of Cdx2 , T , Wnt3a , and Cyp26a1 genes was also confirmed in ES cells by forced expression of Ptf1a . Taken together, these results suggest that ETn insertion induced ectopic expression of Ptf1a , and that following combined partial deficiency of Cdx2 and its downstream target genes caused Sd phenotypes.