L1CAM/Neuroglian controls the axon–axon interactions establishing layered and lobular mushroom body architecture

Siegenthaler, Dominique; Enneking, Eva-Maria; Moreno, Eliza; Pielage, Jan

doi:10.1083/jcb.201407131

Cited by 41 publications

(55 citation statements)

References 72 publications

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“…Mutational analysis of Neuroglian identified a requirement for the ERM-interaction domain, to which Moesin binds, in the establishment of the mushroom body’s highly organized architecture [51]. Neuroglian mutants display severe mushroom body phenotypes including growth and guidance errors, missing lobes and branching defects [50, 51], similar to those herein that result from the modulation of Moesin expression. The deletion of the ERM interaction domain of Neuroglian, however, results in a phenotype in which aberrant axonal projections form a ball-like structure from continuous circular growth in the posterior of the brain [50, 51].…”

Section: Discussionmentioning

confidence: 99%

The ERM protein Moesin is essential for neuronal morphogenesis and long-term memory in Drosophila

Freymuth

Fitzsimons

2017

Mol Brain

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Moesin is a cytoskeletal adaptor protein that plays an important role in modification of the actin cytoskeleton. Rearrangement of the actin cytoskeleton drives both neuronal morphogenesis and the structural changes in neurons that are required for long-term memory formation. Moesin has been identified as a candidate memory gene in Drosophila, however, whether it is required for memory formation has not been evaluated. Here, we investigate the role of Moesin in neuronal morphogenesis and in short- and long-term memory formation in the courtship suppression assay, a model of associative memory. We found that both knockdown and overexpression of Moesin led to defects in axon growth and guidance as well as dendritic arborization. Moreover, reduction of Moesin expression or expression of a constitutively active phosphomimetic in the adult Drosophila brain had no effect on short term memory, but prevented long-term memory formation, an effect that was independent of its role in development. These results indicate a critical role for Moesin in both neuronal morphogenesis and long-term memory formation.Electronic supplementary materialThe online version of this article (10.1186/s13041-017-0322-y) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The ERM protein Moesin is essential for neuronal morphogenesis and long-term memory in Drosophila

Freymuth

Fitzsimons

2017

Mol Brain

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“…STRING analysis of the 26 genes identified in our screen revealed potential mechanistic links between HDAC4 and genes encoding proteins with nuclear functions (Smr, Gcn5, Sin3A, and CrebB), proteins involved in SUMOylation (Nup358 and Ubc9), and proteins that interact with the cytoskeleton or influence cytoskeletal growth (Moesin, Ankyrin, Ankyrin 2, Netrin-B, trio, Sra-1, derailed, and Prosap) (Figure 3). In neurons, the latter group of genes also regulates axon and/or dendritic growth (Harris et al 1996;Bonkowsky et al 1999;Schenck et al 2003;Lee et al 2007;Briancon-Marjollet et al 2008;Iyer et al 2012;Siegenthaler et al 2015;Yasunaga et al 2015).…”

Section: Identification Of Hdac4 Gene Targets In Neuronsmentioning

confidence: 99%

“…Yang et al 2009). Several of these genes including trio (Iyer et al 2012;Shivalkar and Giniger 2012), Netrin B (Harris et al 1996;Mitchell et al 1996), krasavietz (Lee et al 2007;SanchezSoriano et al 2009), and Ankyrin 2 (Siegenthaler et al 2015) regulate axon and/or dendrite growth in Drosophila. Moreover, krasavietz (Dubnau et al 2003) and Ankyrin 2 (Iqbal et al 2013) are also required for memory formation.…”

Section: E/ementioning

confidence: 99%

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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“…Both tagged transgenes are inserted at the same chromosomal location [11, 49], which ensures similar expression strength, and to maximize expression we used established stocks that are homozygous for the Gal4 driver and the UAS-constructs. We live imaged the GF axons in the CvC of one to four day old adult nervous systems.…”

Section: Resultsmentioning

confidence: 99%

Lissencephaly-1 dependent axonal retrograde transport of L1-type CAM Neuroglian in the adult drosophila central nervous system

et al. 2017

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Here, we established the Drosophila Giant Fiber neurons (GF) as a novel model to study axonal trafficking of L1-type Cell Adhesion Molecules (CAM) Neuroglian (Nrg) in the adult CNS using live imaging. L1-type CAMs are well known for their importance in nervous system development and we previously demonstrated a role for Nrg in GF synapse formation. However, in the adult they have also been implicated in synaptic plasticity and regeneration. In addition, to its canonical role in organizing cytoskeletal elements at the plasma membrane, vertebrate L1CAM has also been shown to regulate transcription indirectly as well as directly via its import to the nucleus. Here, we intend to determine if the sole L1CAM homolog Nrg is retrogradley transported and thus has the potential to relay signals from the synapse to the soma. Live imaging of c-terminally tagged Nrg in the GF revealed that there are at least two populations of retrograde vesicles that differ in speed, and either move with consistent or varying velocity. To determine if endogenous Nrg is retrogradely transported, we inhibited two key regulators, Lissencephaly-1 (Lis1) and Dynactin, of the retrograde motor protein Dynein. Similar to previously described phenotypes for expression of poisonous subunits of Dynactin, we found that developmental knock down of Lis1 disrupted GF synaptic terminal growth and that Nrg vesicles accumulated inside the stunted terminals in both mutant backgrounds. Moreover, post mitotic Lis1 knock down in mature GFs by either RNAi or Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) induced mutations, resulted in normal length terminals with fully functional GF synapses which also exhibited severe accumulation of endogenous Nrg vesicles. Thus, our data suggests that accumulation of Nrg vesicles is due to failure of retrograde transport rather than a failure of terminal development. Together with the finding that post mitotic knock down of Lis1 also disrupted retrograde transport of tagged Nrg vesicles in GF axons, it demonstrates that endogenous Nrg protein is transported from the synapse to the soma in the adult central nervous system in a Lis1-dependent manner.

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L1CAM/Neuroglian controls the axon–axon interactions establishing layered and lobular mushroom body architecture

Abstract: Targeted domain-specific mutations and cell type–specific rescue experiments show that L1CAM/Neuroglian is required for axon–axon interactions and yield insights into the cellular mechanisms controlling establishment of the complex mushroom body architecture.

Cited by 41 publications

References 72 publications

The ERM protein Moesin is essential for neuronal morphogenesis and long-term memory in Drosophila

The ERM protein Moesin is essential for neuronal morphogenesis and long-term memory in Drosophila

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

Lissencephaly-1 dependent axonal retrograde transport of L1-type CAM Neuroglian in the adult drosophila central nervous system

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