Transcriptional regulation of TLX2 and impaired intestinal innervation:: possible role of the PHOX2A and PHOX2B genes
Transcriptional regulation of TLX2 and impaired intestinal innervation:: possible role of the PHOX2A and PHOX2B genes
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DOI：
10.1038/sj.ejhg.5201852
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发表时间：
2007-08-01
影响因子：
5.2
通讯作者：
Ceccherini, Isabella
中科院分区：
文献类型：
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作者：
Borghini, Silvia;Di Duca, Marco;Ceccherini, Isabella
TLX2(也称为HOX11L1、NCX和ENX)是一种转录因子，在肠道神经系统的发育中发挥关键作用，这一点已被表现为肠神经节细胞增多症和假性梗阻的小鼠模型所证实。然而，先天性TLX2缺陷已被排除为肠神经元发育不良(IND)或假性梗阻患者肠道运动障碍的主要原因。在论证了同源蛋白PHOX2B对TLX2表达的直接调控之后，在本工作中，我们将重点放在其类似物PHOX2A上。通过共转染、电泳迁移率改变分析和染色质免疫沉淀，我们已经证明PHOX2A和PHOX2B一样，参与了导致TLX2反式激活的级联反应，并可能参与了肠道神经元的分化。基于TLX2基因缺失激活导致肠道神经系统缺陷的假设，PHOX2A和PHOX2B被认为是与IND和假性梗阻相关的新的候选基因，并因此分析了26例特定患者的突变情况。我们已经确定了一个仍未报道的PHOX2A变异体；然而，没有任何对TLX2反式激活的功能影响表明，除PHOX2基因以外的调节因子或效应器必须在相同的途径中发挥作用，可能在此类肠道疾病的发病机制中发挥非多余和直接的作用。
TLX2 (also known as HOX11L1, Ncx and Enx) is a transcription factor playing a crucial role in the development of the enteric nervous system, as confirmed by mice models exhibiting intestinal hyperganglionosis and pseudo-obstruction. However, congenital defects of TLX2 have been excluded as a major cause of intestinal motility disorders in patients affected with intestinal neuronal dysplasia ( IND) or pseudo-obstruction. After demonstrating the direct regulation of TLX2 expression by the homeoprotein PHOX2B, in the present work, we have focused on its paralogue PHOX2A. By co-transfections, electrophoretic mobility shift assays and chromatin immunoprecipitation, we have demonstrated that PHOX2A, like PHOX2B, is involved in the cascade leading to TLX2 transactivation and presumably in the intestinal neuronal differentiation. Based on the hypothesis that missed activation of the TLX2 gene induces the development of enteric nervous system defects, PHOX2A and PHOX2B have been regarded as novel candidate genes involved in IND and pseudo-obstruction and consequently analyzed for mutations in a specific set of 26 patients. We have identified one still unreported PHOX2A variant; however, absence of any functional effect on TLX2 transactivation suggests that regulators or effectors other than the PHOX2 genes must act in the same pathway, likely playing a non redundant and direct role in the pathogenesis of such enteric disorders.