Conditional expression of Wnt9b in Six2-positive cells disrupts stomach and kidney function.
Conditional expression of Wnt9b in Six2-positive cells disrupts stomach and kidney function.
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DOI：
10.1371/journal.pone.0043098
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Rauchman M
中科院分区：
文献类型：
--
作者：
Kiefer SM;Robbins L;Rauchman M
在肾脏发育过程中，规范的Wnt信号激活分化，而转录因子SIX2维持祖细胞库。这些相反的信号有助于调节肾单位的形成，并确保形成完整的肾单位。由于这两个因素控制着肾间充质的不同命运，我们推测在表达SIX2的细胞中过表达Wnt9b会扰乱肾脏的形成，并可能改变其他组织的细胞分化决定。我们创造了一只转基因小鼠，它有条件地在发育中的肾脏Wnt9b中表达规范的Wnt配体。外源基因由cre重组酶激活，表达绿色荧光蛋白。我们首先用HOXB7-cre检测其生物学活性，发现转基因WNT9b能够诱导分化基因，并能挽救Wnt9b−/−纯合子缺陷小鼠的肾脏发育。相反，在使用SIX2-cre的细胞中表达Wnt9b会导致成年小鼠的胃肠道不适和严重的肾功能衰竭。转基因小鼠肾脏有大量的囊状小管，肌酐值(0.652±0.044)高于野生型小鼠(0.119±0.002)。这些动物还表现出幽门括约肌畸形、十二指肠胃反流和远端胃转变为近端命运。将观察到的WNT9b：EGFP转基因基因的表达变化与稳定的β-连环蛋白等位基因进行比较，以确定WNT9b在所分析的组织中激活了典型的Wnt途径。这些结果表明，Wnt9b在SIX2阳性细胞中的表达扰乱了肾脏和胃肠道的细胞命运决定。
During kidney development, canonical Wnt signaling activates differentiation, while the transcription factor Six2 maintains the progenitor pool. These opposing signals help to regulate nephron formation and ensure the full complement of nephrons are formed. Since these two factors control differing fates in kidney mesenchyme, we hypothesized that overexpression of Wnt9b in Six2-expressing cells would disrupt kidney formation and may alter cell differentiation decisions in other tissues. We created a transgenic mouse that conditionally expressed the canonical Wnt ligand in the developing kidney, Wnt9b. The transgene is activated by cre recombinase and expresses GFP. We first tested its biological activity using Hoxb7-cre and found that transgenic Wnt9b was capable of inducing differentiation genes and of rescuing kidney development in Wnt9b−/− homozygous deficient mice. In contrast, expression of Wnt9b in cells using Six2-cre caused gastrointestinal distress and severe renal failure in adult mice. Transgenic kidneys had numerous cystic tubules and elevated creatinine values (0.652±0.044) compared to wild-type mice (0.119±0.002). These animals also exhibited a malformed pyloric sphincter, duodenogastric reflux, and a transformation of the distal stomach into proximal fate. The gene expression changes observed for the Wnt9b:EGFP transgene were compared to a stabilized β-catenin allele to determine that Wnt9b is activating the canonical Wnt pathway in the tissues analyzed. These results demonstrate that expression of Wnt9b in Six2-positive cells disrupts cell fate decisions in the kidney and the gastrointestinal tract.
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