5-HT4 receptor-mediated neuroprotection and neurogenesis in the enteric nervous system of adult mice.
5-HT4 receptor-mediated neuroprotection and neurogenesis in the enteric nervous system of adult mice.
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DOI：
10.1523/jneurosci.1145-09.2009
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发表时间：
2009-08-05
期刊：
影响因子：
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通讯作者：
Gershon MD
中科院分区：
文献类型：
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作者：
Liu MT;Kuan YH;Wang J;Hen R;Gershon MD
虽然成熟的肠神经系统（ENS）已被证明保留干细胞，肠神经发生以前没有被证明在成人。发现野生型（WT）小鼠和缺乏5-HT 4受体（KO）小鼠的肠神经元的相对数量在出生时相似;然而，在WT而不是KO同窝出生后的前4个月期间，ENS神经元的丰度增加。随后，WT和KO中的肠神经元均减少，但在12个月时，WT中的肠神经元数量明显更多。我们测试了刺激5-HT 4受体促进肠神经元存活和/或神经发生的假设。在体外，5-HT 4激动剂增加肠神经元的发育/存活，减少细胞凋亡，并激活CREB。在体内，在WT而非KO小鼠中，5-HT 4激动剂诱导溴脱氧尿苷（BrdU）掺入表达神经元（HuC/D，doublecortin）、神经前体（Sox 10，nestin，Phox 2b）或干细胞（Musashi-1）标志物的细胞中。这是第一次证明成人肠神经发生，我们的研究结果表明，5-HT 4受体所需的出生后ENS的生长和维护。
Although the mature enteric nervous system (ENS) has been shown to retain stem cells, enteric neurogenesis has not previously been demonstrated in adults. The relative number of enteric neurons in wild-type (WT) mice and those lacking 5-HT4 receptors (KO) was found to be similar at birth; however, the abundance of ENS neurons increased during the first 4 months after birth in WT but not KO littermates. Enteric neurons subsequently decreased in both WT and KO but at 12 months were significantly more numerous in WT. We tested the hypothesis that stimulation of the 5-HT4 receptor promotes enteric neuron survival and/or neurogenesis. In vitro, 5-HT4 agonists increased enteric neuronal development/survival, decreased apoptosis, and activated CREB. In vivo, in WT but not KO mice, 5-HT4 agonists induced bromodeoxyuridine (BrdU) incorporation into cells that expressed markers of neurons (HuC/D, doublecortin), neural precursors (Sox10, nestin, Phox2b), or stem cells (Musashi-1). This is the first demonstration of adult enteric neurogenesis; our results suggest that 5-HT4 receptors are required postnatally for ENS growth and maintenance.