Regulatory Mechanisms Controlling Maturation of Serotonin Neuron Identity and Function

Abstract

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.

Serotonergic plasticity in the dorsal raphe nucleus characterizes susceptibility and resilience to anhedonia

“…4A), which encodes a key transcription factor controlling serotonergic identity (Hendricks et al, 1999). PET1 regulates transcription of Tph2, Sert and other components of serotonergic identity (Spencer and Deneris, 2017). As expected, we found that all neurons expressing Tph2 mRNA also expressed Pet1 mRNA ( Fig.…”

Etv1 Controls the Establishment of Non-overlapping Motor Innervation of Neighboring Facial Muscles during Development

“…''Terminal selector'' transcription factors determine the anatomic and functional properties of mature neuronal subpopulations by regulating ''terminal effector'' genes that, in turn, define the cytoarchitectural, electro-physiological, and functional properties of postmitotic, mature neurons (Hobert, 2008;Serrano-Saiz et al, 2018;Spencer and Deneris, 2017). The expression of terminal selectors is sustained over time by feed-forward, autoregulatory loops, through which, they activate their own promoters (Deneris and Hobert, 2014).…”

Global transcriptomic analysis of the arcuate nucleus following chronic glucocorticoid treatment

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