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

尾端退化综合征（CRS）是一种先天性的异质性尾端畸形，包括不同程度的脊柱发育不全、肛肠畸形和泌尿生殖系统异常（Ando T., Semba K.等。mech Dev. 128:129-40）。2011年)。其发病机制尚不清楚。然而，根据对各种携带尾侧发育的小鼠突变体的分析，这可能是胚胎尾侧区域过度生理退化的结果。在小鼠突变体中，丹佛斯短尾（Sd）小鼠被认为是人类CRS的最佳模型。Sd为半显性突变，以脊柱缺损、泌尿生殖缺损、肛门直肠畸形为特征，与人类CRS表现出表型相似性。虽然已知Sd定位于小鼠2号染色体，但对Sd的分子性质知之甚少。在这里，我们展示了在Ptf1a基因附近插入一种类型的反转录转座子。这导致胚胎尾侧Ptf1a基因异位表达，Cdx2及其下游靶点下调，导致Sd小鼠出现特征性表型。因此，Sd突变小鼠将为脊柱、肛门和肾脏的发育提供见解（Semba K. et al.）。科学通报。9:e1003204。2013年)。

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.).