Targeted deletion of Hand2 in enteric neural precursor cells affects its functions in neurogenesis, neurotransmitter specification and gangliogenesis, causing functional aganglionosis
Targeted deletion of Hand2 in enteric neural precursor cells affects its functions in neurogenesis, neurotransmitter specification and gangliogenesis, causing functional aganglionosis
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DOI：
10.1242/dev.060053
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发表时间：
2011-11-01
期刊：
影响因子：
4.6
通讯作者：
Howard, Marthe J.
中科院分区：
文献类型：
--
作者：
Lei, Jun;Howard, Marthe J.
神经嵴中bHLH DNA结合蛋白Hand 2的靶向缺失可能通过调节从神经前体细胞到神经元的转变来影响肠神经系统（ENS）的发育。我们通过靶向表达巢蛋白的神经前体细胞（NEP）中的Hand 2缺失来验证这一假设。突变小鼠显示异常ENS发育，导致致命的神经源性假性梗阻。NEP细胞来源的神经元的神经发生确定了第二个nestin非表达神经前体细胞（NNEP）在ENS. There是大量的补偿来自NEP池的神经元的损失，但这是不足以消除的负面影响Hand 2删除。Hand 2介导的增殖调节影响神经前体和神经元数量。NEP细胞衍生的神经胶质细胞的分化显著降低，没有来自NNEP细胞库的补偿。我们的数据表明NEPs和NNEPs的差异发育潜力; NNEPs优先分化为神经元，而NEPs产生神经元和神经胶质细胞。Hand 2的缺失也导致NOS和VIP的完全丧失以及胆碱乙酰转移酶和钙视黄蛋白表达的显著降低，表明Hand 2在神经递质指定和/或表达中的作用。丧失手2导致发育中的神经网络明显中断，例如缺乏肌间神经丛和纤维广泛过度生长。因此，Hand 2对于发育中的ENS中的神经发生、神经递质指定和神经网络模式化是必不可少的。
Targeted deletion of the bHLH DNA-binding protein Hand2 in the neural crest, impacts development of the enteric nervous system (ENS), possibly by regulating the transition from neural precursor cell to neuron. We tested this hypothesis by targeting Hand2 deletion in nestin-expressing neural precursor (NEP) cells. The mutant mice showed abnormal ENS development, resulting in lethal neurogenic pseudo-obstruction. Neurogenesis of neurons derived from NEP cells identified a second nestin non-expressing neural precursor (NNEP) cell in the ENS. There was substantial compensation for the loss of neurons derived from the NEP pool by the NNEP pool but this was insufficient to abrogate the negative impact of Hand2 deletion. Hand2-mediated regulation of proliferation affected both neural precursor and neuron numbers. Differentiation of glial cells derived from the NEP cells was significantly decreased with no compensation from the NNEP pool of cells. Our data indicate differential developmental potential of NEPs and NNEPs; NNEPs preferentially differentiate as neurons, whereas NEPs give rise to both neurons and glial cells. Deletion of Hand2 also resulted in complete loss of NOS and VIP and a significant decrease in expression of choline acetyltransferase and calretinin, demonstrating a role for Hand2 in neurotransmitter specification and/or expression. Loss of Hand2 resulted in a marked disruption of the developing neural network, exemplified by lack of a myenteric plexus and extensive overgrowth of fibers. Thus, Hand2 is essential for neurogenesis, neurotransmitter specification and neural network patterning in the developing ENS.