Department of Animal Genetics, Graduate School of Natural Science and Technology, Okayama University, Okayama, Japan.
Am J Pathol. 2010 Aug;177(2):822-8. doi: 10.2353/ajpath.2010.091278. Epub 2010 Jul 8.
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.
利钠肽受体 B（NPR-B）对 C 型利钠肽（CNP）具有高亲和力，并合成细胞内 cGMP，可能参与胃肠道（GIT）调节。NPR-B 编码基因（Npr2）的突变等位基因负责短肢侏儒症（SLW）小鼠的表型。这种常染色体隐性基因（slw/slw）的纯合性导致断奶前的侏儒症和死亡，因为胃中牛奶潴留和肠扩张。为了阐明 CNP/NPR-B 信号与 GIT 功能之间的关系，我们研究了 Npr2 突变与 slw/slw 小鼠 GIT 表型之间的关系。突变体的幽门和大肠对 CNP 刺激没有反应；此外，它们表现出幽门管腔变窄，圆形平滑肌细胞排列不规则。GIT 组织中 cGMP 和神经元标志物分布的比较证实了神经元组织中 cGMP 的表达。突变体的 Auerbach 神经丛和黏膜下组织不表达 cGMP，而表达 Ca(2+)。相比之下，正常小鼠（对照）的组织既表达 cGMP 又表达 Ca(2+)。测序显示，致病的 Npr2 突变是外显子 8 中的 7 个碱基缺失，导致移码和提前终止密码子出现。因此，slw/slw 小鼠的 GIT 表型是由于 Npr2 突变导致的 CNP/NPR-B 信号缺陷。这些结果有助于更好地理解 CNP/NPR-B 信号在 GIT 运动中的作用。
