Hedgehog and Fgf signaling pathways regulate the development of tphR-expressing serotonergic raphe neurons in zebrafish embryos.
Hedgehog and Fgf signaling pathways regulate the development of tphR-expressing serotonergic raphe neurons in zebrafish embryos.
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DOI：
10.1002/neu.20023
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发表时间：
2004-09-05
期刊：
影响因子：
--
通讯作者：
Wilson, SW
中科院分区：
文献类型：
--
作者：
Teraoka, H;Russell, C;Regan, J;Chandrasekhar, A;Concha, ML;Yokoyama, R;Higashi, K;Take-uchi, M;Dong, W;Hiraga, T;Holder, N;Wilson, SW
5-羟色胺（5-HT）在许多行为过程（包括睡眠、进食和情绪）的生理调节中起着重要作用，但对多巴胺能神经元在发育过程中产生的遗传机制知之甚少。在本研究中，我们研究了斑马鱼的多巴胺能神经元的发育。从受精后45小时（HPF）在腹侧后脑中缝，下丘脑，松果体器官，和顶盖前区检测到神经元表现出5 HT-免疫反应（5 HT-IR）。色氨酸羟化酶编码在5 HT合成中起作用的限速酶。作为这项研究的一部分，我们克隆和分析了一个新的斑马鱼tph基因命名为tphR。与其他两个斑马鱼tph基因（tphD 1和tphD 2）不同，tphR在多巴胺能中缝核神经元中表达，类似于哺乳动物物种中的tph基因。tphR也在松果体器官中表达，在那里它可能参与导致褪黑激素合成的途径。为了更好地了解参与诱导的促肾上腺素能表型的信号传导途径，我们分析了胚胎中的tphR表达和5 HT-IR，其中Hh或Fgf信号被废除。在缺乏Ace/Fgf 8或转录因子Noi/Pax2.1活性的突变体中，后脑5 HT神经元严重减少，所述转录因子Noi/Pax2.1调节Ace/Fgf 8以及可能编码信号蛋白的其他基因的表达。类似地，在缺乏Hh活性的胚胎中不存在Hh能中缝神经元，这证实了Hh信号在这些细胞的诱导中的保守作用。相反，Hh通路的过度激活增加了多巴胺能神经元的数量。在哺乳动物中，我们的研究结果是一致的转录因子Nk2.2和Gata 3作用下游的Hh活性的发育中的多巴胺能中缝神经元。我们的研究结果表明，参与诱导后脑神经元的途径可能是保守的所有脊椎动物，并帮助建立斑马鱼作为模型系统，研究这一重要的神经元类。
Serotonin (5HT) plays major roles in the physiological regulation of many behavioral processes, including sleep, feeding, and mood, but the genetic mechanisms by which serotonergic neurons arise during development are poorly understood. In the present study, we have investigated the development of serotonergic neurons in the zebrafish. Neurons exhibiting 5HT-immunoreactivity (5HT-IR) are detected from 45 h postfertilization (hpf) in the ventral hindbrain raphe, the hypothalamus, pineal organ, and pretectal area. Tryptophan hydroxylases encode rate-limiting enzymes that function in the synthesis of 5HT. As part of this study, we cloned and analyzed a novel zebrafish tph gene named tphR. Unlike two other zebrafish tph genes (tphD1 and tphD2), tphR is expressed in serotonergic raphe neurons, similar to tph genes in mammalian species. tphR is also expressed in the pineal organ where it is likely to be involved in the pathway leading to synthesis of melatonin. To better understand the signaling pathways involved in the induction of the serotonergic phenotype, we analyzed tphR expression and 5HT-IR in embryos in which either Hh or Fgf signals are abrogated. Hindbrain 5HT neurons are severely reduced in mutants lacking activity of either Ace/Fgf8 or the transcription factor Noi/Pax2.1, which regulates expression of ace/fgf8, and probably other genes encoding signaling proteins. Similarly, serotonergic raphe neurons are absent in embryos lacking Hh activity confirming a conserved role for Hh signals in the induction of these cells. Conversely, over-activation of the Hh pathway increases the number of serotonergic neurons. As in mammals, our results are consistent with the transcription factors Nk2.2 and Gata3 acting downstream of Hh activity in the development of serotonergic raphe neurons. Our results show that the pathways involved in induction of hindbrain serotonergic neurons are likely to be conserved in all vertebrates and help establish the zebrafish as a model system to study this important neuronal class.
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