A spontaneous and novel Pax3 mutant mouse that models Waardenburg syndrome and neural tube defects.
A spontaneous and novel Pax3 mutant mouse that models Waardenburg syndrome and neural tube defects.
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一种自发的新型 Pax3 突变小鼠，可模拟 Waardenburg 综合征和神经管缺陷。
DOI：
10.1016/j.gene.2016.12.037
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发表时间：
2017
期刊：
影响因子：
3.5
通讯作者：
T. Yoshikawa
中科院分区：
文献类型：
--
作者：
T. Ohnishi;I. Miura;Hisako Ohba;Chie Shimamoto;Y. Iwayama;S. Wakana;T. Yoshikawa
背景负责啮齿动物色素沉着表型减少的基因与人类发育缺陷有关，例如瓦登堡综合征，患者表现出先天性耳聋以及主要与神经嵴发育缺陷有关的各种异常。 目的在这项研究中，我们鉴定了一种自发突变小鼠系Rwa，其在C57BL/6N遗传背景下，在小鼠腹部、白色手指和尾巴上显示出可变的白斑。还观察到卷尾和脊柱裂，尽管外显率较低。这些表型主要由后代遗传。我们寻找观察到的表型的遗传机制。方法我们利用实验室新开发的快速小鼠基因图谱系统来识别负责基因。结果我们检测到 1 号染色体内的一个区域作为因果突变的可能位点。使用间隔标记的密集作图将基因座缩小到 670 kbp 区域，包含四个基因，其中包括 Pax3，该基因已知与 I 型和 III 型 Waardenburg 综合征有关。 Pax3 的广泛突变筛选检测到 841 bp 缺失，跨越该基因的启动子区域和内含子 1。 Pax3 的缺陷等位基因名为 Pax3Rwa，缺乏第一个编码外显子，并且与表型完美共分离，证实了其因果性质。 Rwamice 的遗传背景几乎与近交 C57BL/6N 相同。结论这些结果突出表明 Pax3Rwamice 作为分析涉及 Pax3 的生物过程的有益工具，特别是神经嵴细胞和黑素细胞的发育和迁移。
BackgroundGenes responsible for reduced pigmentation phenotypes in rodents are associated with human developmental defects, such as Waardenburg syndrome, where patients display congenital deafness along with various abnormalities mostly related to neural crest development deficiency.ObjectiveIn this study, we identified a spontaneous mutant mouse lineRwa, which displays variable white spots on mouse bellies and white digits and tail, on a C57BL/6N genetic background. Curly tail andspina bifidawere also observed, although at a lower penetrance. These phenotypes were dominantly inherited by offspring. We searched for the genetic mechanism of the observed phenotypes.MethodsWe harnessed a rapid mouse gene mapping system newly developed in our laboratories to identify a responsible gene.ResultsWe detected a region within chromosome 1 as a probable locus for the causal mutation. Dense mapping using interval markers narrowed the locus down to a 670-kbp region, containing four genes includingPax3, a gene known to be implicated in the types I and III Waardenburg syndrome. Extensive mutation screening ofPax3detected an 841-bp deletion, spanning the promoter region and intron 1 of the gene. The defective allele ofPax3, namedPax3Rwa, lacked the first coding exon and co-segregated perfectly with the phenotypes, confirming its causal nature. The genetic background ofRwamice is almost identical to that of inbred C57BL/6N.ConclusionThese results highlightPax3Rwamice as a beneficial tool for analyzing biological processes involvingPax3, in particular the development and migration of neural crest cells and melanocytes.