Upregulation of the Nr2f1-A830082K12Rik gene pair in murine neural crest cells results in a complex phenotype reminiscent of Waardenburg syndrome type 4.
Upregulation of the Nr2f1-A830082K12Rik gene pair in murine neural crest cells results in a complex phenotype reminiscent of Waardenburg syndrome type 4.
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DOI：
10.1242/dmm.026773
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发表时间：
2016-11-01
影响因子：
4.3
通讯作者：
Pilon N
中科院分区：
文献类型：
--
作者：
Bergeron KF;Nguyen CM;Cardinal T;Charrier B;Silversides DW;Pilon N
Waardenburg综合征是一种神经系统疾病，其特征是皮肤和头发色素沉着以及内耳缺陷。在4型中，这些缺陷与先天性巨结肠病（一种以结肠远端神经节缺失为特征的疾病，引发功能性肠梗阻）共病。在这里，我们报告通过插入突变筛选神经嵴细胞（NCC）发育相关基因获得的斑点小鼠系是Waardenburg综合征4型的模型。我们发现，位点插入突变导致NCCs中由转录因子编码Nr2f1和反义长链非编码RNA A830082K12Rik组成的重叠基因对过表达，其机制涉及解除这些基因的抑制。与先前描述的Nr2f1在促进中枢神经系统胶质细胞形成中的作用一致，我们进一步发现，肠道神经系统的ncc来源的祖细胞由于在胶质细胞中过早分化而不能完全定植于Spot胚胎肠道。综上所述，我们的数据因此确定了Nr2f1-A830082K12Rik基因对的沉默元件作为Waardenburg综合征4型的新候选位点。摘要：一项正向遗传筛选方法揭示了一种新的机制，涉及Nr2f1和/或A830082K12Rik在神经嵴细胞中的过表达，可能促进Waardenburg综合征和巨结肠病的发展。
Waardenburg syndrome is a neurocristopathy characterized by a combination of skin and hair depigmentation, and inner ear defects. In the type 4 form, these defects show comorbidity with Hirschsprung disease, a disorder marked by an absence of neural ganglia in the distal colon, triggering functional intestinal obstruction. Here, we report that the Spot mouse line – obtained through an insertional mutagenesis screen for genes involved in neural crest cell (NCC) development – is a model for Waardenburg syndrome type 4. We found that the Spot insertional mutation causes overexpression of an overlapping gene pair composed of the transcription-factor-encoding Nr2f1 and the antisense long non-coding RNA A830082K12Rik in NCCs through a mechanism involving relief of repression of these genes. Consistent with the previously described role of Nr2f1 in promoting gliogenesis in the central nervous system, we further found that NCC-derived progenitors of the enteric nervous system fail to fully colonize Spot embryonic guts owing to their premature differentiation in glial cells. Taken together, our data thus identify silencer elements of the Nr2f1-A830082K12Rik gene pair as new candidate loci for Waardenburg syndrome type 4. Summary: A forward genetic screen approach unveils a new mechanism, involving Nr2f1 and/or A830082K12Rik overexpression in neural crest cells, that could promote development of Waardenburg syndrome and Hirschsprung disease.
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影响因子：
5.2
作者：
Bondurand, Nadege;Fouquet, Virginie;Pingault, Veronique
通讯作者：
Pingault, Veronique
影响因子：
1.7
作者：
HILDESHEIMER, M;MAAYAN, Z;GOODMAN, RM
通讯作者：
GOODMAN, RM
影响因子：
4.5
作者：
Bergeron, Karl-F.;Cardinal, Tatiana;Pilon, Nicolas
通讯作者：
Pilon, Nicolas
在肠道中建立大脑：肠神经系统的发展。
影响因子：
3.5
作者：
Goldstein AM;Hofstra RM;Burns AJ
通讯作者：
Burns AJ
DOI：
10.1152/ajpgi.00452.2012
发表时间：
2013-07-01
期刊：
American journal of physiology. Gastrointestinal and liver physiology
影响因子：
--
作者：
Lake JI;Heuckeroth RO
通讯作者：
Heuckeroth RO