Department of Neurosciences and Program in Neurosciences and Neurodegenerative Diseases, University of Toledo Health Sciences Campus, Toledo, OH 43614, USA.
Development. 2011 Nov;138(21):4789-800. doi: 10.1242/dev.060053.
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.
靶向敲除神经嵴中 bHLH DNA 结合蛋白 Hand2 会影响肠神经系统（ENS）的发育，这可能是通过调节神经前体细胞向神经元的转化来实现的。我们通过靶向巢蛋白表达的神经前体细胞（NEP）中的 Hand2 缺失来验证这一假设。突变小鼠表现出 ENS 发育异常，导致致命的神经源性假性肠梗阻。源自 NEP 细胞的神经元的神经发生鉴定出 ENS 中的第二个巢蛋白非表达神经前体细胞（NNEP）。NNEP 池对源自 NEP 池的神经元的缺失有大量补偿，但不足以消除 Hand2 缺失的负面影响。Hand2 介导的增殖调节影响神经前体细胞和神经元的数量。源自 NEP 细胞的神经胶质细胞的分化显著减少，而 NNEP 池的细胞没有补偿。我们的数据表明 NEPs 和 NNEPs 具有不同的发育潜力；NNEPs 优先分化为神经元，而 NEPs 则产生神经元和神经胶质细胞。Hand2 的缺失也导致 NOS 和 VIP 的完全缺失，以及胆碱乙酰转移酶和钙结合蛋白的表达显著减少，表明 Hand2 在神经递质的特化和/或表达中起作用。Hand2 的缺失导致正在发育的神经网络发生明显破坏，表现为缺少肌间神经丛和纤维广泛过度生长。因此，Hand2 对于 ENS 中神经发生、神经递质特化和神经网络模式形成是必不可少的。
