Gastrointestinal Tract Disorder in Natriuretic Peptide Receptor B Gene Mutant Mice
Gastrointestinal Tract Disorder in Natriuretic Peptide Receptor B Gene Mutant Mice
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DOI：
10.2353/ajpath.2010.091278
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发表时间：
2010-08-01
影响因子：
6
通讯作者：
Kunieda, Tetsuo
中科院分区：
文献类型：
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作者：
Sogawa, Chizuru;Abe, Asaki;Kunieda, Tetsuo
利钠肽B受体(NPR-B)与C型利钠肽(CNP)具有高亲和力，可在细胞内合成cGMP，可能参与胃肠道(GIT)的调节。NPR-B编码基因的一个突变等位基因(Npr2)导致了短肢侏儒症(SLW)小鼠的表型。这种常染色体隐性基因(SLW/SLW)的纯合子会导致侏儒症和断奶前死亡，这是因为乳汁滞留在胃里和肠道膨胀。为了阐明CNP/NPR-B信号与Git功能的关系，我们研究了SLW/SLW小鼠Npr2突变与Git表型的关系。突变体的幽门和大肠对CNP刺激没有反应；此外，它们还显示幽门管腔变窄，环状肌细胞随机排列。比较cGMP和神经元标志物在GIT组织中的分布，证实了cGMP在神经元组织中的表达。突变体的奥尔巴赫神经丛和粘膜下组织不表达cGMP，表达Ca(2+)。相反，正常小鼠(对照组)同时表达cGMP和Ca(2+)。测序结果显示，Npr2突变是外显子8的7个碱基缺失，导致码型移位和过早终止密码子的出现。因此，SLW/SLW小鼠的GIT表型是由于Npr2突变引起的CNP/NPR-B信号缺陷所致。这些结果有助于更好地理解CNP/NPR-B信号在胃肠动力中的作用。(Am J Pathol2010,177：822-828；DOI：10.2353/ajpath.2010.091278)
Natriuretic peptide receptor B (NPR-B), which has high affinity for C-type natriuretic peptide (CNP) and synthesizes intracellular cGMP, may be involved in gastrointestinal tract (GIT) regulation. A mutant allele of the NPR-B-encoding gene (Npr2) is responsible for the phenotype of the short-limb dwarfism (SLW) mouse. Homozygosity for this autosomal-recessive gene (slw/slw) leads to dwarfism and death before weaning because of milk retention in the stomach and intestinal distention. To elucidate the relationship between CNP/NPR-B signaling and GIT function, we investigated the association between Npr2 mutation and the GIT phenotype in slw/slw mice. The pylorus and large intestine of the mutants did not respond to CNP stimulation; further, they showed pyloric lumen narrowing with randomly aligned circular muscle cells. Comparison of the cGMP and neuronal marker distribution in GIT tissues confirmed cGMP expression in neuronal tissues. An Auerbach's plexus and submucosal tissues of the mutants didn't express cGMP and expressed Ca(2+). In contrast, those of normal mice (controls) expressed both cGMP and Ca(2+). Sequencing revealed that the causative Npr2 mutation was a 7-base deletion in exon 8, resulting in a frameshift and premature termination codon appearance. Therefore, the GIT phenotype of slw/slw mice is because of a CNP/NPR-B-signaling defect caused by an Npr2 mutation. These results facilitate better understanding of the role of CNP/NPR-B signaling in GIT motility. (Am J Pathol 2010, 177:822-828; DOI: 10.2353/ajpath.2010.091278)