Autonomic neurocristopathy-associated mutations in PHOX2B dysregulate Sox10 expression
Autonomic neurocristopathy-associated mutations in PHOX2B dysregulate Sox10 expression
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DOI：
10.1172/jci63401
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发表时间：
2012-09-01
影响因子：
15.9
通讯作者：
Enomoto, Hideki
中科院分区：
文献类型：
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作者：
Nagashimada, Mayumi;Ohta, Hiroshi;Enomoto, Hideki
自主神经系统中最常见的神经嵴病形式是导致肠神经节先天性缺失的先天性巨结肠病（HSCR）和神经母细胞瘤（NB），起源于交感神经节和肾上腺髓质的儿童肿瘤。这些疾病的风险显着增加的先天性中枢性低通气综合征（CCHS）的患者窝藏非多聚丙氨酸重复扩展配对样同源框2b（PHOX 2B）基因突变，但发病机制的分子机制仍然未知。我们发现将PHOX 2B的非多聚丙氨酸重复扩增突变引入小鼠Phox 2b位点概括了与HSCR和NB相关的CCHS的临床特征。在突变胚胎，肠和交感神经节祖细胞表现出持续的性别决定区Y（SRY）盒10（Sox 10）的表达，与受损的增殖和偏向分化。神经胶质细胞谱系PHOX 2B的非多聚丙氨酸重复扩增突变以显性负性方式降低了野生型PHOX 2B对其已知靶点多巴胺β-羟化酶（DBH）的反式激活。此外，引入的突变将PHOX 2B对Sox 10增强子的转录作用从抑制转化为反式激活。总的来说，这些数据表明，PHOX 2B的非聚丙氨酸重复扩增突变是显性失活和功能获得性突变。我们的研究结果还表明，SOX 10的调节PHOX 2B是关键的自主神经节的发展和发病机制。
The most common forms of neurocristopathy in the autonomic nervous system are Hirschsprung disease (HSCR), resulting in congenital loss of enteric ganglia, and neuroblastoma (NB), childhood tumors originating from the sympathetic ganglia and adrenal medulla. The risk for these diseases dramatically increases in patients with congenital central hypoventilation syndrome (CCHS) harboring a nonpolyalanine repeat expansion mutation of the Paired-like homeobox 2b (PHOX2B) gene, but the molecular mechanism of pathogenesis remains unknown. We found that introducing nonpolyalanine repeat expansion mutation of the PHOX2B into the mouse Phox2b locus recapitulates the clinical features of the CCHS associated with HSCR and NB. In mutant embryos, enteric and sympathetic ganglion progenitors showed sustained sex-determining region Y (SRY) box10 (Sox10) expression, with impaired proliferation and biased differentiation toward. the glial lineage. Nonpolyalanine repeat expansion mutation of PHOX2B reduced transactivation of wild-type PHOX2B on its known target, dopamine beta-hydroxylase (DBH), in a dominant-negative fashion. Moreover, the introduced mutation converted the transcriptional effect of PHOX2B on a Sox10 enhancer from repression to transactivation. Collectively, these data reveal that nonpolyalanine repeat expansion mutation of PHOX2B is both a dominant-negative and gain-of-function mutation. Our results also demonstrate that Sox10 regulation by PHOX2B is pivotal for the development and pathogenesis of the autonomic ganglia.