Ectopic expression of Ptf1a induces spinal defects, urogenital defects, and anorectal malformations in Danforth's short tail mice.
Ectopic expression of Ptf1a induces spinal defects, urogenital defects, and anorectal malformations in Danforth's short tail mice.
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DOI：
10.1371/journal.pgen.1003204
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Yamamura K
中科院分区：
文献类型：
--
作者：
Semba K;Araki K;Matsumoto K;Suda H;Ando T;Sei A;Mizuta H;Takagi K;Nakahara M;Muta M;Yamada G;Nakagata N;Iida A;Ikegawa S;Nakamura Y;Araki M;Abe K;Yamamura K
丹佛斯短尾（Sd）是小鼠2号染色体上的一种半显性突变，其特征是脊柱缺陷、泌尿生殖缺陷和肛门直肠畸形。然而，负责Sd表型的基因是未知的。在这项研究中，我们确定了Sd突变的分子基础。通过定位克隆，我们确定了一个早期的转座子插入在Sd的候选基因座约12 kb的Ptf 1a的上游。我们发现，转座子的插入导致三个相邻的基因，Gm 13344，Gm 13336，和Ptf 1a，在Sd突变胚胎的过表达，并没有引起Sd表型的破坏，因为尚未未知的基因在候选位点。使用多个敲除和敲入小鼠模型，我们证明了Ptf 1a，但不是GM 13344或GM 13336，在脊索，后肠，泄殖腔，和中肾的错误表达是足以复制的Sd表型。Ptf 1a在尾胚胎中的异位表达导致Cdx 2及其下游靶基因T、Wnt 3a和Cyp 26 a1的表达减弱;我们得出结论，这是Sd表型的分子基础。对Sd突变小鼠的分析将提供对脊柱、肛门和肾脏发育的深入了解。尾部退化综合征（CRS）是一种先天性尾部异常的异质性星座，包括不同程度的脊柱发育不全，肛门直肠畸形和泌尿生殖系统异常。其发病机制尚不清楚。然而，根据对携带尾部发育不全的各种小鼠突变体的分析，这可能是胚胎尾部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是一种半显性突变，以脊柱缺陷、泌尿生殖缺陷和肛门直肠畸形为特征，因此显示出与人CRS的表型相似性。虽然已知Sd定位于小鼠2号染色体，但对突变的分子性质知之甚少。在这里，我们展示了一种类型的反转录转座子附近的Ptf 1a基因的插入。这导致Ptf 1a基因在胚胎尾部区域的异位表达和Cdx 2及其下游靶点的下调，导致Sd小鼠的特征表型。因此，Sd突变小鼠将提供对脊柱、肛门和肾脏发育的深入了解。
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. Caudal regression syndrome (CRS) is a congenital heterogeneous constellation of caudal anomalies that includes varying degrees of agenesis of the spinal column, anorectal malformations, and genitourinary anomalies. Its pathogenesis is unclear. However, it could be the result of excessive physiologic regression of the embryonic caudal region based on analyses of the various mouse mutants carrying caudal agenesis. Among the mouse mutants, the Danforth's short tail (Sd) mouse is considered a best model for human CRS. Sd is a semidominant mutation, characterized by spinal defects, urogenital defects, and anorectal malformations, thus showing phenotypic similarity to human CRS. Although Sd is known to map to mouse chromosome 2, little is known about the molecular nature of the mutation. 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 and downregulation of Cdx2 and its downstream targets, leading to characteristic phenotypes in Sd mouse. Thus, Sd mutant mice will provide insight into the development of the spinal column, anus, and kidney.
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