Spencer William C, Deneris Evan S
Department of Neurosciences, Case Western Reserve UniversityCleveland, OH, United States.
Front Cell Neurosci. 2017 Jul 19;11:215. doi: 10.3389/fncel.2017.00215. eCollection 2017.
The brain serotonin (5-hydroxytryptamine; 5-HT) system has been extensively studied for its role in normal physiology and behavior, as well as, neuropsychiatric disorders. The broad influence of 5-HT on brain function, is in part due to the vast connectivity pattern of 5-HT-producing neurons throughout the CNS. 5-HT neurons are born and terminally specified midway through embryogenesis, then enter a protracted period of maturation, where they functionally integrate into CNS circuitry and then are maintained throughout life. The transcriptional regulatory networks controlling progenitor cell generation and terminal specification of 5-HT neurons are relatively well-understood, yet the factors controlling 5-HT neuron maturation are only recently coming to light. In this review, we first provide an update on the regulatory network controlling 5-HT neuron development, then delve deeper into the properties and regulatory strategies governing 5-HT neuron maturation. In particular, we discuss the role of the 5-HT neuron terminal selector transcription factor (TF) Pet-1 as a key regulator of 5-HT neuron maturation. Pet-1 was originally shown to positively regulate genes needed for 5-HT synthesis, reuptake and vesicular transport, hence 5-HT neuron-type transmitter identity. It has now been shown to regulate, both positively and negatively, many other categories of genes in 5-HT neurons including ion channels, GPCRs, transporters, neuropeptides, and other transcription factors. Its function as a terminal selector results in the maturation of 5-HT neuron excitability, firing characteristics, and synaptic modulation by several neurotransmitters. Furthermore, there is a temporal requirement for Pet-1 in the control of postmitotic gene expression trajectories thus indicating a direct role in 5-HT neuron maturation. Proper regulation of the maturation of cellular identity is critical for normal neuronal functioning and perturbations in the gene regulatory networks controlling these processes may result in long-lasting changes in brain function in adulthood. Further study of 5-HT neuron gene regulatory networks is likely to provide additional insight into how neurons acquire their mature identities and how terminal selector-type TFs function in postmitotic vertebrate neurons.
大脑血清素（5-羟色胺；5-HT）系统因其在正常生理和行为以及神经精神疾病中的作用而受到广泛研究。5-HT对大脑功能的广泛影响，部分归因于整个中枢神经系统中产生5-HT的神经元的广泛连接模式。5-HT神经元在胚胎发育中期产生并最终确定，然后进入一个漫长的成熟阶段，在这个阶段它们在功能上整合到中枢神经系统回路中，并在整个生命过程中得以维持。控制5-HT神经元祖细胞生成和最终确定的转录调控网络相对较为清楚，但控制5-HT神经元成熟的因素直到最近才被发现。在这篇综述中，我们首先提供关于控制5-HT神经元发育的调控网络的最新信息，然后更深入地探讨控制5-HT神经元成熟的特性和调控策略。特别是，我们讨论了5-HT神经元终末选择转录因子（TF）Pet-1作为5-HT神经元成熟的关键调节因子的作用。Pet-1最初被证明能正向调节5-HT合成、再摄取和囊泡运输所需的基因，因此与5-HT神经元类型的递质身份有关。现在已经证明它能正向和负向调节5-HT神经元中的许多其他基因类别，包括离子通道、G蛋白偶联受体、转运体、神经肽和其他转录因子。它作为终末选择因子的功能导致5-HT神经元兴奋性、放电特性以及几种神经递质对突触的调节作用成熟。此外，在有丝分裂后基因表达轨迹的控制中对Pet-1有时间上的要求，这表明它在5-HT神经元成熟中起直接作用。细胞身份成熟的适当调控对于正常神经元功能至关重要，而控制这些过程的基因调控网络中的扰动可能导致成年期大脑功能的长期变化。对5-HT神经元基因调控网络的进一步研究可能会提供更多关于神经元如何获得其成熟身份以及终末选择型转录因子在有丝分裂后脊椎动物神经元中如何发挥作用的见解。
