dCREB2-Mediated Enhancement of Memory Formation

Tubon, Thomas C.; Zhang, Jiabin; Friedman, Eugenia; Jin, Haining; Gonzales, Erin D.; Zhou, Hong; Drier, Diana; Gerstner, Jason R.; Paulson, Emily A.; Fropf, Robin; Yin, Jingyi

doi:10.1523/jneurosci.4387-12.2013

Cited by 34 publications

(37 citation statements)

References 73 publications

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“…In Figure 5B, the commercially available (Santa Cruz), mammalian CREB antibody (αC21) was used. Its validity in flies has been previously demonstrated (Tubon et al 2013). …”

Section: Methodsmentioning

confidence: 88%

“…Serum was passed over a peptide column containing the unphosphorylated peptide, and the flow through fraction was bound and eluted from the phospho-peptide column. The αATG2 antibody has been described previously (Tubon et al 2013). In brief, it was raised against a peptide that is just C-terminal to the ATG2 codon.…”

Section: Methodsmentioning

confidence: 99%

“…However, this single gene produces multiple protein isoforms. Two of these isoforms, activator and blocker, have been shown to enhance or suppress memory, respectively, when overexpressed (Yin et al, 1994; Yin et al, 1995a; Tubon et al 2013). While these isoforms have been shown to interact in vitro and in transfected cells (Yin et al, 1995b), the specific endogenous isoforms and molecular mechanisms involved during memory formation remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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Nuclear gating of a Drosophila dCREB2 activator is involved in memory formation

Fropf

Tubon

Yin

2013

Neurobiology of Learning and Memory

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The transcription factor CREB is an important regulator of many adaptive processes in neurons, including sleep, cellular homeostasis, and memory formation. The Drosophila dCREB2 family includes multiple protein isoforms generated from a single gene. Overexpression of an activator or blocker isoform has been shown to enhance or block memory formation, but the molecular mechanisms underlying these phenomena remain unclear. In the present study, we generate isoform-specific antibodies and new transgenic flies to track and manipulate the activity of different dCREB2 isoforms during memory formation. We find that nuclear accumulation of a dCREB2 activator-related species, p35+, is dynamically regulated during memory formation. Furthermore, various dCREB2 genetic manipulations that enhance or block memory formation correspondingly increase or decrease p35+ levels in the nucleus. Finally, we show that overexpression of S6K can enhance memory formation and increase p35+ nuclear abundance. Taken together, these results suggest that regulation of dCREB2 localization may be a key molecular convergence point in the coordinated host of events that lead to memory formation.

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“…In Figure 5B, the commercially available (Santa Cruz), mammalian CREB antibody (αC21) was used. Its validity in flies has been previously demonstrated (Tubon et al 2013). …”

Section: Methodsmentioning

confidence: 88%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Nuclear gating of a Drosophila dCREB2 activator is involved in memory formation

Fropf

Tubon

Yin

2013

Neurobiology of Learning and Memory

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“…This may indicate that HDAC4 influences the SUMOylation state of a limited number of targets. Thus we next examined the impact of HDAC4 overexpression on the SUMOylation of candidate proteins CaMKII, MEF2, and CREB, neuronal proteins that are involved in memory formation (Mehren and Griffith 2004;Barbosa et al 2008;Cole et al 2012;Tubon et al 2013), which also have been demonstrated to interact physically with HDAC4 (Miska et al 1999;McKinsey et al 2000;Backs et al 2008;Li et al 2012), and are SUMO substrates (Long and Griffith 2000;Gregoire and Yang 2005;Zhao et al 2005;Chen et al 2014). However, we did not observe any species indicative of a SUMOylated form of CREB or CaMKII with standard ( Figure 6B) or long exposures ( Figure 6C).…”

Section: Hdac4 and Ubc9 Interact During Ltm Formationmentioning

confidence: 88%

Long-Term Memory inDrosophilaIs Influenced by Histone Deacetylase HDAC4 Interacting with SUMO-Conjugating Enzyme Ubc9

et al. 2016

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HDAC4 is a potent memory repressor with overexpression of wild type or a nuclear-restricted mutant resulting in memory deficits. Interestingly, reduction of HDAC4 also impairs memory via an as yet unknown mechanism. Although histone deacetylase family members are important mediators of epigenetic mechanisms in neurons, HDAC4 is predominantly cytoplasmic in the brain and there is increasing evidence for interactions with nonhistone proteins, suggesting HDAC4 has roles beyond transcriptional regulation.To that end, we performed a genetic interaction screen in Drosophila and identified 26 genes that interacted with HDAC4, including Ubc9, the sole SUMO E2-conjugating enzyme. RNA interference-induced reduction of Ubc9 in the adult brain impaired long-term memory in the courtship suppression assay, a Drosophila model of associative memory. We also demonstrate that HDAC4 and Ubc9 interact genetically during memory formation, opening new avenues for investigating the mechanisms through which HDAC4 regulates memory formation and other neurological processes.KEYWORDS histone deacetylase; SUMOylation; plasticity; neuron; memory T HE histone deacetylase HDAC4 is widely expressed in neurons throughout the brain (Darcy et al. 2010) and an increasing body of evidence indicates that HDAC4 plays important roles in neurological function Chen and Cepko 2009;Kim et al. 2012;Li et al. 2012;Sando et al. 2012;Sarkar et al. 2014). To that end, we recently demonstrated that in Drosophila, RNA interference (RNAi)-mediated knockdown of HDAC4 in the adult brain impairs long-term memory (LTM) in the courtship suppression assay, a model of associative memory (Fitzsimons et al. 2013). Similarly in humans, loss of one copy of HDAC4 correlates with brachydactyly mental retardation syndrome (BDMR), the neurological symptoms of which include intellectual disability and autism (Williams et al. 2010;Morris et al. 2012;Villavicencio-Lorini et al. 2013), and in mice, conditional knockout of HDAC4 in the brain results in impairments in hippocampal-dependent associative LTM . Despite this growing evidence of a critical role, the mechanism(s) through which HDAC4 positively influences LTM is unknown. This is in part because HDAC4 exists in both nuclear and cytoplasmic pools, and under basal conditions, the majority of HDAC4 is localized to the cytoplasm (Chawla et al. 2003;Darcy et al. 2010). Given the predominant nonnuclear localization, particularly the concentration of HDAC4 at dendritic spines (Darcy et al. 2010), we hypothesize that cytoplasmic HDAC4 is required in memory formation; however, the mechanisms through which HDAC4 acts outside the nucleus are unknown.The nuclear role of HDAC4 is less of an enigma. When in the nucleus, HDAC4 acts as a transcriptional repressor; although vertebrate HDAC4 is catalytically inactive as a histone deacetylase, rather it facilitates changes in gene expression through direct binding and inhibition of transcription factors such as MEF2 (Miska et al. 1999;Wang et al. 1999;Lu et al. 2000). As described abov...

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“…When in the nucleus, HDAC4 binds to and represses MEF2 in vivo (Sando et al, 2012), and it also interacts with CREB in rodent brain (Li et al, 2012), and these interactions are conserved as HDAC4 genetically interacts with both CREB and MEF2 in Drosophila photoreceptors (unpublished data) and colocalizes with MEF2 in Drosophila Kenyon cell nuclei (Fitzsimons et al, 2013). CREB is a key transcription factor that governs the expression of genes required for synaptic plasticity and its positive role in formation of long-term memory has been well established in many model systems (Bourtchuladze et al, 1994;Dash, Hochner, & Kandel, 1990;Tubon et al, 2013). Inhibition of CREB by HDAC4 may therefore be a mechanism by which HDAC4 represses memory formation.…”

Section: How Does Hdac4 Regulate Memory?mentioning

confidence: 98%

The Class IIa histone deacetylase HDAC4 and neuronal function: Nuclear nuisance and cytoplasmic stalwart?

Fitzsimons

2015

Neurobiology of Learning and Memory

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dCREB2-Mediated Enhancement of Memory Formation

Cited by 34 publications

References 73 publications

Nuclear gating of a Drosophila dCREB2 activator is involved in memory formation

Nuclear gating of a Drosophila dCREB2 activator is involved in memory formation

Long-Term Memory inDrosophilaIs Influenced by Histone Deacetylase HDAC4 Interacting with SUMO-Conjugating Enzyme Ubc9

The Class IIa histone deacetylase HDAC4 and neuronal function: Nuclear nuisance and cytoplasmic stalwart?

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