Transcribing the connectome: roles for transcription factors and chromatin regulators in activity-dependent synapse development

Chen, Liangfu; Zhou, Allen; West, Anne E.

doi:10.1152/jn.00067.2017

“…These structures are serially linked in the pathway for odor perception (Power, 1946): odor detection occurs in olfactory neurons of the third antennal segment, which synapse onto projection neurons in the antennal lobe glomeruli that in turn send sensory information to the mushroom body calyces. Mammalian MEF2 expression is maintained into adulthood and is important for neuronal plasticity (Flavell et al, 2006;Sivachenko et al, 2013;Chen et al, 2016;Chen et al, 2017). Together with the D-MEF2 expression pattern that we found, these data suggest that D-MEF2 is important for plasticity differences between the mushroom body lobes (Yu et al, 2006) in olfactory learning.…”

Section: Mushroom Body Expression Pattern Of D-mef2supporting

confidence: 73%

Drosophila mef2is essential for normal mushroom body and wing development

Crittenden

¹

,

Skoulakis

²

,

Goldstein

³

et al. 2018

Preprint

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MEF2 (myocyte enhancer factor 2) transcription factors are found in the brain and muscle of insects and vertebrates and are essential for the differentiation of multiple cell types. We show that in the fruitfly Drosophila, MEF2 is essential for normal development of wing veins, and for mushroom body formation in the brain. In embryos mutant for D-mef2, there was a striking reduction in the number of mushroom body neurons and their axon bundles were not detectable. D-MEF2 expression coincided with the formation of embryonic mushroom bodies and, in larvae, expression onset was confirmed to be in post-mitotic neurons. With a D-mef2 point mutation that disrupts nuclear localization, we find that D-MEF2 is restricted to a subset of Kenyon cells that project to the α/β, and γ axonal lobes of the mushroom bodies, but not to those forming the α'/β' lobes. Our findings that ancestral mef2 is specifically important in dopamine-receptive neurons has broad implications for its function in mammalian neurocircuits.

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“…5 Immediate early genes that are poised for transcriptional activation have distinct chromatin structure and may not need Sirt1 for activation to occur. 50 This may imply that the chromatin structure at the Hr38 locus in Sirt1 mutants is by and in large intact. However, induction and termination of immediate early gene expression may be controlled by distinct chromatin-based mechanisms operating on the same gene locus.…”

Section: Discussionmentioning

confidence: 99%

“…39 Hr38 in Drosophila controls cuticle development and glycogen storage, and its expression is regulated by neuronal activity, social cues, light and extreme drops in temperature. 50 This may imply that the chromatin structure at the Hr38 locus in Sirt1 mutants is by and in large intact. One way ANOVA/Tukey's, n = 6 biological replicates.…”

Section: Sirt1 Terminates Ethanol-induction Of Hr38 To Promote Ethamentioning

confidence: 99%

Mef2 induction of the immediate early gene Hr38/Nr4a is terminated by Sirt1 to promote ethanol tolerance

Adhikari

¹

,

Orozco

²

,

Randhawa

³

et al. 2018

Genes Brain and Behavior

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Drug naïve animals given a single dose of ethanol show changed responses to subsequent doses, including the development of ethanol tolerance and ethanol preference. These simple forms of behavioral plasticity are due in part to changes in gene expression and neuronal properties. Surprisingly little is known about how ethanol initiates changes in gene expression or what the changes do. Here we demonstrate a role in ethanol plasticity for Hr38, the sole Drosophila homolog of the mammalian Nr4a1/2/3 class of immediate early response transcription factors. Acute ethanol exposure induces transient expression of Hr38 and other immediate early neuronal activity genes. Ethanol activates the Mef2 transcriptional activator to induce Hr38, and the Sirt1 histone/protein deacetylase is required to terminate Hr38 induction. Loss of Hr38 decreases ethanol tolerance and causes precocious but short-lasting ethanol preference. Similarly, reduced Mef2 activity in all neurons or specifically in the mushroom body α/β neurons decreases ethanol tolerance; Sirt1 promotes ethanol tolerance in these same neurons. Genetically decreasing Hr38 expression levels in Sirt1 null mutants restores ethanol tolerance, demonstrating that both induction and termination of Hr38 expression are important for behavioral plasticity to proceed. These data demonstrate that Hr38 functions as an immediate early transcription factor that promotes ethanol behavioral plasticity.

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“…Hr38 induction by ethanol, however, appears to be independent of Sirt1. This may be due to the distinct chromatin structure at immediate early gene loci (Chen et al 2017). Moreover, the loss of Sirt1 deacetylase activity in Sirt1 mutants may directly result in prolonged acetylation of the Hr38 locus and its continued transcriptional activation.…”

Section: Discussionmentioning

confidence: 99%

Mef2 induction of the immediate early gene Hr38/Nr4a is terminated by Sirt1 to promote ethanol tolerance

Adhikari

¹

,

Orozco

²

,

Wolf

³

2017

Preprint

View full text Add to dashboard Cite

Drug naïve animals given a single dose of ethanol show changed responses to subsequent doses, including the development of ethanol tolerance and ethanol preference. These simple forms of behavioral plasticity are due in part to changes in gene expression and neuronal properties. Surprisingly little is known about how ethanol initiates changes in gene expression or what the changes do. Here we demonstrate a role in ethanol plasticity for Hr38, the sole Drosophila homolog of the mammalian Nr4a1/2/3 class of immediate early response transcription factors. Acute ethanol exposure induces transient expression of Hr38 and other immediate early neuronal activity genes. Ethanol activates the Mef2 transcriptional activator to induce Hr38, and the Sirt1 histone/protein deacetylase terminates Hr38 induction. Loss of Hr38 decreases ethanol tolerance and causes precocious but shortlasting ethanol preference. Similarly, reduced Mef2 activity in all neurons or specifically in the mushroom body α/β neurons decreases ethanol tolerance; Sirt1 promotes ethanol tolerance in these same neurons. Genetically decreasing Hr38 expression levels in Sirt1 null mutants restores ethanol tolerance, demonstrating that both induction and termination of Hr38 expression are important for behavioral plasticity to proceed. These data demonstrate that Hr38 functions as an immediate early transcription factor that promotes ethanol behavioral plasticity. IntroductionEthanol, one of the most widely used and frequently abused addictive drugs, is a small molecule that diffuses rapidly throughout the body and that binds to an as yet incompletely defined spectrum of molecules. Its effects vary based on dose, exposure time and pattern, an individuals' history of intake, and their genetic makeup. This complexity of action has hampered progress in reducing the prevalence of alcohol use disorders through rational interventions (Edenberg & Foroud 2013).One approach forward is to define, in detail, the stimulusresponse relationship for ethanol in ethanol naïve animals. While the first ethanol exposure rarely leads directly to alcoholism, it does cause changes in behavior that reflect changes in brain function; these changes provide an altered substrate for subsequent intake and promote addiction risk. Furthermore, many genes are oppositely regulated by acute ethanol exposure and in ethanol withdrawal (Palmisano & Pandey 2017). Practically, this suggests that detailed mechanistic understanding of acute ethanol exposure action, especially when coupled to measures of behavioral plasticity, will provide insight into the more complex mechanisms underlying addiction. One form of ethanolinduced behavioral plasticity is tolerance, the acquired resistance to the inebriating and sedating properties of ethanol (Fadda & Rossetti 1998). Ethanol tolerance facilitates increased intake, a risk factor for later developing alcohol use disorders.Drugs of abuse, including ethanol, cause changes in gene expression in the brain that can alter the properties of the brain. Drosophila me...

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Transcribing the connectome: roles for transcription factors and chromatin regulators in activity-dependent synapse development

Cited by 30 publications

References 142 publications

Drosophila mef2is essential for normal mushroom body and wing development

Drosophila mef2is essential for normal mushroom body and wing development

Mef2 induction of the immediate early gene Hr38/Nr4a is terminated by Sirt1 to promote ethanol tolerance

Mef2 induction of the immediate early gene Hr38/Nr4a is terminated by Sirt1 to promote ethanol tolerance

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