Adult Raphe-Specific Deletion of Lmx1b Leads to Central Serotonin Deficiency

Song, Ning‐Ning; Xiu, Jian Bo; Huang, Ying; Chen, Jia Yin; Zhang, Lei; Gutknecht, Lise; Lesch, Klaus‐Peter; Li, He; Ding, Yu

doi:10.1371/journal.pone.0015998

Cited by 66 publications

(70 citation statements)

References 33 publications

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“…We have demonstrated that Lmx1a is coexpressed with Chga and 5-HT in enterochromaffin cells and is essential for the expression of Tph1, the gut-specific 5HT-synthesizing gene. Interestingly, the Lmx1a paralog Lmx1b regulates Tph2 (Song et al, 2011) and serotonergic neuron development downstream of Nkx2.2 in the brain (Cheng et al, 2003;Song et al, 2011). Since Lmx1b is only expressed at extremely low levels in the intestine (Makarev and Gorivodsky, 2014), it is likely that Lmx1a performs analogous functions downstream of Nkx2.2 for intestinal 5-HT + cell development.…”

Section: Discussionmentioning

confidence: 99%

Lmx1a functions in intestinal serotonin-producing enterochromaffin cells downstream of Nkx2.2

et al. 2016

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Intestinal hormone-producing cells represent the largest endocrine system in the body, but remarkably little is known about enteroendocrine cell type specification in the embryo and adult. We analyzed stage-and cell type-specific deletions of Nkx2.2 and its functional domains in order to characterize its role in the development and maintenance of enteroendocrine cell lineages in the mouse duodenum and colon. Although Nkx2.2 regulates enteroendocrine cell specification in the duodenum at all stages examined, it controls the differentiation of progressively fewer enteroendocrine cell populations when deleted from Ngn3 + progenitor cells or in the adult duodenum. During embryonic development Nkx2.2 regulates all enteroendocrine cell types, except gastrin and preproglucagon. In developing Ngn3+ enteroendocrine progenitor cells, Nkx2.2 is not required for the specification of neuropeptide Y and vasoactive intestinal polypeptide, indicating that a subset of these cell populations derive from an Nkx2.2-independent lineage. In adult duodenum, Nkx2.2 becomes dispensable for cholecystokinin and secretin production. In all stages and Nkx2.2 mutant conditions, serotonin-producing enterochromaffin cells were the most severely reduced enteroendocrine lineage in the duodenum and colon. We determined that the transcription factor Lmx1a is expressed in enterochromaffin cells and functions downstream of Nkx2.2. Lmx1a-deficient mice have reduced expression of Tph1, the rate-limiting enzyme for serotonin biosynthesis. These data clarify the function of Nkx2.2 in the specification and homeostatic maintenance of enteroendocrine populations, and identify Lmx1a as a novel enterochromaffin cell marker that is also essential for the production of the serotonin biosynthetic enzyme Tph1.

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Section: Discussionmentioning

confidence: 99%

Lmx1a functions in intestinal serotonin-producing enterochromaffin cells downstream of Nkx2.2

et al. 2016

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“…However the overall number of serotonergic neurons is not affected by deleting Lmx1b, and Pet1 promoter expression in the adult brain is independent of Lmx1b. Reduction in central serotonin levels seems to be the consequence of TrpH2 downregulation (Song et al 2011 ). In fact Pet1 in the brain is necessary for terminal differentiation of serotonergic neuron phenotype during embryonic development (Hendricks et al 2003 ).…”

Section: Serotonin Neurotransmissionmentioning

confidence: 97%

“…Pet1 RNA co-localizes with TrpH-positive neurons in raphe nuclei. Loss of Pet1 in the serotonergic neurons leads to a decrease of TrpH2 expression but no change in Lmx1b expression (Song et al 2011 ). Virtually serotonergic and nonserotonergic axons innervate distinct but partially overlapping fi elds within vestibular nuclei (Halberstadt and Balaban 2007 ).…”

Section: Serotonin Neurotransmissionmentioning

confidence: 97%

Tryptophan-Related Signaling Molecules: Targets and Functions

Engin

2015

Tryptophan Metabolism: Implications for Biological Processes, Health and Disease

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Most of the daily dietary tryptophan (Trp) is oxidatively degraded through the kynurenine (Kyn) pathway, and the remaining may be consumed either in serotonin synthesis or in conversion into melatonin through the methoxyindole pathway. Trp degradation products along the Kyn pathway include three neuroactive metabolites: the neuroinhibitory agent kynurenic acid (KA), the free radical generator 3-hydroxykynurenine (3HK), and the excitotoxin quinolinic acid (QA). Kyn is the major metabolite of Trp and is readily transported across the blood-brain barrier into the brain where it can be further metabolized in perivascular macrophages, microglia, and astrocytes, also to generate neuroactive intermediates. In contrast to Kyn, QA, KA, and 3-hydroxyanthranilic acid (3HAA) penetrate through the blood-brain barrier only poorly due to its polar nature. Although the cytokines do not pass through the blood-brain barrier, their signals reach the brain through humoral, neural, and cellular pathways and stimulate Trp degradation by interacting with a cytokine network in the brain. The induction of Kyn pathway by indoleamine 2,3-dioxygenase (IDO) activity exhausts L -Trp in the medium and produces toxic metabolites. While Kyn to Trp ratio refl ects IDO activity, Kyn to KA ratio indicates the neurotoxic challenge. Alpha7 nicotinic acetylcholine receptor (alpha7nAChR) constitutes a crucial link between excessive KA formation and reduction in glutamate. KA-induced reduction in prefrontal glutamate levels emerges as a result of alpha7nAChR inhibition. Changes in the endogenous concentrations of KA, as a potent alpha7nAChR and N-methyl-D -aspartate (NMDA) receptor antagonist, affect extracellular dopamine levels in the brain. The entire monoaminergic neurotransmission involves functional interactions between serotonin, norepinephrine, and dopamine systems (Fig. 1.1 ). Serotonin transporter (SERT) reuptakes biogenic amine neurotransmitters following release in the nervous systems and terminates the action of serotonin. SERT can be regulated by a membrane-bound G-proteincoupled receptor, and this occurs via nitric oxide (NO) and cyclic guanosine monophosphate (cGMP). Desensitization and re-sensitization of G-protein-coupled

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“…68 In this model, recombination was shown to be specific for serotonergic neurons in the DR and raphe magnus (RM), but only 85% of TPH2 expressing neurons co-expressed the floxed reporter gene after TMX treatment.…”

Section: Bac-pet1-creert2mentioning

confidence: 99%

“…68 One limitation of this mouse line is its FVB/N background used for the generation of founder lines. Most floxed mice are generated on a C57BL/6 background, which has become the most widely used strain for developmental and behavioral studies.…”

Section: Bac-pet1-creert2mentioning

confidence: 99%

Beyond Gene Inactivation: Evolution of Tools for Analysis of Serotonergic Circuitry

Hainer

Mosienko

Koutsikou

et al. 2015

ACS Chem. Neurosci.

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In the brain, serotonin (5-hydroxytryptamine, 5-HT) controls a multitude of physiological and behavioral functions. Serotonergic neurons in the raphe nuclei give rise to a complex and extensive network of axonal projections throughout the whole brain. A major challenge in the analysis of these circuits is to understand how the serotonergic networks are linked to the numerous functions of this neurotransmitter. In the past, many studies employed approaches to inactivate different genes involved in serotonergic neuron formation, 5-HT transmission, or 5-HT metabolism. Although these approaches have contributed significantly to our understanding of serotonergic circuits, they usually result in life-long gene inactivation. As a consequence, compensatory changes in serotonergic and other neurotransmitter systems may occur and complicate the interpretation of the observed phenotypes. To dissect the complexity of the serotonergic system with greater precision, approaches to reversibly manipulate subpopulations of serotonergic neurons are required. In this review, we summarize findings on genetic animal models that enable control of 5-HT neuronal activity or mapping of the serotonergic system. This includes a comparative analysis of several mouse and rat lines expressing Cre or Flp recombinases under Tph2, Sert, or Pet1 promoters with a focus on specificity and recombination efficiency. We further introduce applications for Cre-mediated cell-type specific gene expression to optimize spatial and temporal precision for the manipulation of serotonergic neurons. Finally, we discuss other temporally regulated systems, such as optogenetics and designer receptors exclusively activated by designer drugs (DREADD) approaches to control 5-HT neuron activity.

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Adult Raphe-Specific Deletion of Lmx1b Leads to Central Serotonin Deficiency

Cited by 66 publications

References 33 publications

Lmx1a functions in intestinal serotonin-producing enterochromaffin cells downstream of Nkx2.2

Lmx1a functions in intestinal serotonin-producing enterochromaffin cells downstream of Nkx2.2

Tryptophan-Related Signaling Molecules: Targets and Functions

Beyond Gene Inactivation: Evolution of Tools for Analysis of Serotonergic Circuitry

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