RET and NRG1 interplay in Hirschsprung disease
RET and NRG1 interplay in Hirschsprung disease
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DOI：
10.1007/s00439-013-1272-9
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发表时间：
2013-05-01
期刊：
影响因子：
5.3
通讯作者：
Garcia-Barcelo, Maria-Merce
中科院分区：
文献类型：
--
作者：
Gui, Hongsheng;Tang, Wai-Kiu;Garcia-Barcelo, Maria-Merce
先天性巨结肠（Hirschsprung disease，HSCR）是一种复杂的肠神经系统（enteric nervous system，ENS）遗传性疾病，其特征是肠神经元沿着不同长度的肠缺失。虽然参与ENS发育的几个基因的编码序列（CDS）中的罕见变体（RV）会导致疾病，但仅报告了RET（主要HSCR基因）和NRG 1的常见变体（CV）与HSCR的相关性。重要的是，这两个基因的CDS中的RV也与该疾病相关。为了评估在HSCR患者中鉴定的不同类型的RET和NRG 1变体之间的独立和联合效应，我们使用了254例中国散发性HSCR患者和143例种族匹配的对照，这些患者的RET和/或NRG 1变体基因型（罕见和常见）可用。四个遗传风险因素的定义和相互作用的影响进行了建模，使用条件Logistic回归分析和成对Kendall相关性。我们的分析揭示了RET CV与RET RV、NRG 1 CV或NRG 1 RV的联合效应。为了评估遗传相互作用是否转化为功能相互作用，用NRG 1（ErbB 2配体）或/和GDNF（Ret配体）处理从胚胎肠道分离的小鼠神经嵴细胞（NCC;肠神经元前体），并在随后的神经分化过程中进行监测。Nrg 1抑制GDNF诱导的神经元分化，GDNF通过下调其受体ErbB 2的表达来负性调节Nrg 1信号。这些初步数据表明，神经发生/胶质细胞生成的平衡是ENS发育的关键。
Hirschsprung disease (HSCR, aganglionic megacolon) is a complex genetic disorder of the enteric nervous system (ENS) characterized by the absence of enteric neurons along a variable length of the intestine. While rare variants (RVs) in the coding sequence (CDS) of several genes involved in ENS development lead to disease, the association of common variants (CVs) with HSCR has only been reported for RET (the major HSCR gene) and NRG1. Importantly, RVs in the CDS of these two genes are also associated with the disorder. To assess independent and joint effects between the different types of RET and NRG1 variants identified in HSCR patients, we used 254 Chinese sporadic HSCR patients and 143 ethnically matched controls for whom the RET and/or NRG1 variants genotypes (rare and common) were available. Four genetic risk factors were defined and interaction effects were modeled using conditional logistic regression analyses and pair-wise Kendall correlations. Our analysis revealed a joint effect of RET CVs with RET RVs, NRG1 CVs or NRG1 RVs. To assess whether the genetic interaction translated into functional interaction, mouse neural crest cells (NCCs; enteric neuron precursors) isolated from embryonic guts were treated with NRG1 (ErbB2 ligand) or/and GDNF (Ret ligand) and monitored during the subsequent neural differentiation process. Nrg1 inhibited the Gdnf-induced neuronal differentiation and Gdnf negatively regulated Nrg1-signaling by down-regulating the expression of its receptor, ErbB2. This preliminary data suggest that the balance neurogenesis/gliogenesis is critical for ENS development.