A Differentially Autoregulated<i>Pet-1</i>Enhancer Region Is a Critical Target of the Transcriptional Cascade That Governs Serotonin Neuron Development

Scott, Michael M.; Krueger, Katherine C.; Deneris, Evan S.

doi:10.1523/jneurosci.4979-04.2005

Cited by 58 publications

(89 citation statements)

References 49 publications

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“…Animals identified as sick by veterinary staff were not used for experiments. Note that the expression pattern of ePet transgenics including ePet-cre (18,19,54) compare favorably with many other commonly used pancreas-, islet-, and β-cell-specific transgenic mouse lines, which, like ePet, also express in serotonergic brainstem nuclei as well as in the pancreas. However, unlike ePet, when used as cre drivers other pancreatic promoters frequently cause recombination in other CNS locations including the hypothalamus (Fig.…”

Section: Methodsmentioning

confidence: 78%

Gα _i/o -coupled receptor signaling restricts pancreatic β-cell expansion

Berger

Scheel

Macias

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Gi-GPCRs, G protein-coupled receptors that signal via Gα proteins of the i/o class (Gαi/o), acutely regulate cellular behaviors widely in mammalian tissues, but their impact on the development and growth of these tissues is less clear. For example, Gi-GPCRs acutely regulate insulin release from pancreatic β cells, and variants in genes encoding several Gi-GPCRs—including the α-2a adrenergic receptor, ADRA2A—increase the risk of type 2 diabetes mellitus. However, type 2 diabetes also is associated with reduced total β-cell mass, and the role of Gi-GPCRs in establishing β-cell mass is unknown. Therefore, we asked whether Gi-GPCR signaling regulates β-cell mass. Here we show that Gi-GPCRs limit the proliferation of the insulin-producing pancreatic β cells and especially their expansion during the critical perinatal period. Increased Gi-GPCR activity in perinatal β cells decreased β-cell proliferation, reduced adult β-cell mass, and impaired glucose homeostasis. In contrast, Gi-GPCR inhibition enhanced perinatal β-cell proliferation, increased adult β-cell mass, and improved glucose homeostasis. Transcriptome analysis detected the expression of multiple Gi-GPCRs in developing and adult β cells, and gene-deletion experiments identified ADRA2A as a key Gi-GPCR regulator of β-cell replication. These studies link Gi-GPCR signaling to β-cell mass and diabetes risk and identify it as a potential target for therapies to protect and increase β-cell mass in patients with diabetes.

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Section: Methodsmentioning

confidence: 78%

Gα _i/o -coupled receptor signaling restricts pancreatic β-cell expansion

Berger

Scheel

Macias

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…These results suggest that ets-5 expression is subject to autoregulation and that tagged ETS-5 shows reduced autoregulation relative to wild-type ETS-5. Many of the mammalian ETS genes, including a closely related mammalian ortholog of ets-5, Pet-1 (human ortholog, FEV), are also subject to autoregulation (Scott et al 2005;Swiers et al 2006;Liu et al 2010), suggesting that the mechanisms underlying ETS gene function may be at least partly conserved across phyla. However, it is also possible that the reduced expression of ets-5::mCherry in the ets-5 mutant background instead results from reduced stability or functionality of the tagged ETS-5 protein in the absence of wild-type ETS-5.…”

Section: Autoregulation Of Ets-5 Expression In Bag Neuronsmentioning

confidence: 99%

“…ETS-5 is one member of a large family of ETS transcription factors defined by an 85 amino acid winged helix-turn-helix DNA binding domain that is conserved in mammals, Drosophila, and C. elegans (Macleod et al 1992;Hollenhorst et al 2011). Close orthologs of ETS-5 have been shown to regulate cellular differentiation and proliferation in mammals (Pereira et al 1999;Scott et al 2005;Liu et al 2010). Our results demonstrate a novel role for ETS-domain transcription factors in the development and function of gas-detecting sensory neurons in C. elegans and raise the possibility that ETS proteins might also regulate gas sensing in mammals.…”

mentioning

confidence: 99%

Differentiation of Carbon Dioxide-Sensing Neurons in Caenorhabditis elegans Requires the ETS-5 Transcription Factor

2011

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Many animals sense environmental gases such as carbon dioxide and oxygen using specialized populations of gas-sensing neurons. The proper development and function of these neurons is critical for survival, as the inability to respond to changes in ambient carbon dioxide and oxygen levels can result in reduced neural activity and ultimately death. Despite the importance of gas-sensing neurons for survival, little is known about the developmental programs that underlie their formation. Here we identify the ETS-family transcription factor ETS-5 as critical for the normal differentiation of the carbon dioxide-sensing BAG neurons in Caenorhabditis elegans. Whereas wild-type animals show acute behavioral avoidance of carbon dioxide, ets-5 mutant animals do not respond to carbon dioxide. The ets-5 gene is expressed in BAG neurons and is required for the normal expression of the BAG neuron gene battery. ets-5 may also autoregulate its expression in BAG neurons. ets-5 is not required for BAG neuron formation, indicating that it is specifically involved in BAG neuron differentiation and the maintenance of BAG neuron cell fate. Our results demonstrate a novel role for ETS genes in the development and function of gas-detecting sensory neurons.

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“…Pet1 drives the expression of genes involved in 5-HT identity, namely the biosynthetic enzyme, tryptophan hydroxylase (Tph2), and the 5-HT plasma membrane transporter (Scl6a4 ) (Hendricks et al, 2003, Liu et al, 2010. However, a contingent of raphe neurons acquires a 5-HT phenotype in the Pet1-knock-out mice (Hendricks et al, 2003;Scott et al, 2005), suggesting that this may reveal a cryptic heterogeneity of the 5-HT raphe neurons.…”

Section: Introductionmentioning

confidence: 99%

A Genetically Defined Morphologically and Functionally Unique Subset of 5-HT Neurons in the Mouse Raphe Nuclei

Kiyasova¹,

Fernandez²,

Lainé³

et al. 2011

J. Neurosci.

125

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Heterogeneity of central serotonin (5-HT) raphe neurons is suggested by numerous lines of evidence, but its genetic basis remains elusive.The transcription factor Pet1 is required for the acquisition of serotonergic identity in a majority of neurons in the raphe nuclei. Nevertheless, a subset of 5-HT neurons differentiates in Pet1 knock-out mice. We show here that these residual 5-HT neurons outline a unique subpopulation of raphe neurons with highly selective anatomical targets and characteristic synaptic differentiations. In Pet1 knock-out mice, 5-HT innervation strikingly outlines the brain areas involved in stress responses with dense innervation to the basolateral amygdala, the paraventricular nucleus of the hypothalamus, and the intralaminar thalamic nuclei. In these regions, 5-HT terminals establish asymmetric synaptic junctions. This target selectivity could not be related to altered growth of the remaining 5-HT neurons, as indicated by axon tracing and cell culture analyses. The residual 5-HT axon terminals are functional with maintained release properties in vitro and in vivo. The functional consequence of this uneven distribution of 5-HT innervation on behavior was characterized. Pet1 knock-out mice showed decreased anxiety behavior in novelty exploration and increased fear responses to conditioned aversive cues. Overall, our findings lead us to propose the existence of Pet1-dependent and Pet1-resistant 5-HT neurons targeting different brain centers that might delineate the anatomical basis for a dual serotonergic control on stress responses.

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A Differentially AutoregulatedPet-1Enhancer Region Is a Critical Target of the Transcriptional Cascade That Governs Serotonin Neuron Development

Cited by 58 publications

References 49 publications

Gα _i/o -coupled receptor signaling restricts pancreatic β-cell expansion

Gα _i/o -coupled receptor signaling restricts pancreatic β-cell expansion

Differentiation of Carbon Dioxide-Sensing Neurons in Caenorhabditis elegans Requires the ETS-5 Transcription Factor

A Genetically Defined Morphologically and Functionally Unique Subset of 5-HT Neurons in the Mouse Raphe Nuclei

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A Differentially AutoregulatedPet-1Enhancer Region Is a Critical Target of the Transcriptional Cascade That Governs Serotonin Neuron Development

Cited by 58 publications

References 49 publications

Gα i/o -coupled receptor signaling restricts pancreatic β-cell expansion

Gα i/o -coupled receptor signaling restricts pancreatic β-cell expansion

Differentiation of Carbon Dioxide-Sensing Neurons in Caenorhabditis elegans Requires the ETS-5 Transcription Factor

A Genetically Defined Morphologically and Functionally Unique Subset of 5-HT Neurons in the Mouse Raphe Nuclei

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Gα _i/o -coupled receptor signaling restricts pancreatic β-cell expansion

Gα _i/o -coupled receptor signaling restricts pancreatic β-cell expansion