The Genetic Analysis of Functional Connectomics in Drosophila

Meinertzhagen, Ian A.; Lee, Chi-Hon

doi:10.1016/b978-0-12-404742-6.00003-x

Cited by 35 publications

(27 citation statements)

References 286 publications

(332 reference statements)

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“…This suggests that these particular astrocytes might bridge the function between these two brain areas, which is consistent with previous publications that imply a close functional relationship between these brain areas (Omoto et al, 2015). Based on these results, we anticipate that this synthetic genetic system will be useful for investigating cell-cell interactions during development in vivo, and has the potential to unveil wiring diagrams of neurons in brain circuits (Meinertzhagen and Lee, 2012;Lichtman and Denk, 2011).…”

Section: Introductionsupporting

confidence: 90%

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Monitoring cell-cell contacts in vivo in transgenic animals

Huang¹,

Velho²,

Lois³

2016

Journal of Cell Science

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We used a synthetic genetic system based on ligand-induced intramembrane proteolysis to monitor cell-cell contacts in animals. Upon ligand-receptor interaction in sites of cell-cell contact, the transmembrane domain of an engineered receptor is cleaved by intramembrane proteolysis and releases a protein fragment that regulates transcription in the interacting partners. We demonstrate that the system can be used to regulate gene expression between interacting cells, both in vitro and in vivo, in transgenic Drosophila. We show that the system allows for detection of interactions between neurons and glia in the Drosophila nervous system. In addition, we observed that when the ligand is expressed in subsets of neurons with a restricted localization in the brain it leads to activation of transcription in a selected set of glial cells that interact with those neurons. This system will be useful to monitor cell-cell interactions in animals, and can be used to genetically manipulate cells that interact with one another.

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Section: Introductionsupporting

confidence: 90%

“…Finally, there is an urgent need for new methods to map synaptic connectivity in neural circuits (Meinertzhagen and Lee, 2012;Lichtman and Denk, 2011). It is generally agreed that identifying how neurons in those circuits are connected to one another is crucial to understanding the computations that take place in brain circuits.…”

Section: Discussionmentioning

confidence: 99%

Monitoring cell-cell contacts in vivo in transgenic animals

Huang¹,

Velho²,

Lois³

2016

Journal of Cell Science

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“…Drosophila , with its compact nervous system, wide range of visual behaviors and a plethora of sophisticated genetic tools for manipulation of circuit function is excellently positioned to fill this gap between circuit and behavior (reviewed in Borst, 2009; Meinertzhagen & Lee, 2012). The fly visual system is comprised of the compound eye and four optic neuropils – the lamina, medulla, lobula and lobula plate.…”

Section: Introductionmentioning

confidence: 99%

Multiple Redundant Medulla Projection Neurons Mediate Color Vision inDrosophila

Melnattur

Pursley

Lin

et al. 2014

Journal of Neurogenetics

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The receptor mechanism for color vision has been extensively studied. In contrast, the circuit(s) that transform(s) photoreceptor signals into color percepts to guide behavior remain(s) poorly characterized. Using intersectional genetics to inactivate identified subsets of neurons, we have uncovered the first-order interneurons that are functionally required for hue discrimination in Drosophila. We developed a novel aversive operant conditioning assay for intensity independent color discrimination (true color vision) in Drosophila. Single flying flies are magnetically tethered in an arena surrounded by blue and green LEDs. The flies’ optomotor response is used to determine the blue-green isoluminant intensity. Flies are then conditioned to discriminate between equiluminant blue or green stimuli. Wild-type flies are successfully trained in this paradigm when conditioned to avoid either blue or green. Functional color entrainment requires the function of the narrow spectrum photoreceptors R8 and/or R7, and is within a limited range, intensity independent, suggesting that it is mediated by a color vision system. The medulla projection neurons, Tm5a/b/c and Tm20, receive direct inputs from R7 or R8 photoreceptors and indirect input from the broad spectrum photoreceptors R1-R6 via the lamina neuron L3. Genetically inactivating these four classes of medulla projection neurons abolished color learning. However, inactivation of subsets of these neurons is insufficient to block color learning, suggesting that true color vision is mediated by multiple redundant pathways. We hypothesize that flies represent color along multiple axes at the first synapse in the fly visual system. The apparent redundancy in learned color discrimination sharply contrasts with innate UV spectral preference, which is dominated by a single pathway from the amacrine neuron Dm8 to the Tm5c projection neurons.

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“…schizophrenia | neuroligin | cerebellin | LRRTM | autism N eurons form highly specific and complex patterns of synaptic connections that underlie all brain function (1)(2)(3)(4)(5). Such specific connections require trillions of chemically differentiated synapses whose identity may be shaped by interactions of specific pre-and postsynaptic signaling molecules, especially cell-adhesion molecules.…”

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confidence: 99%

Cartography of neurexin alternative splicing mapped by single-molecule long-read mRNA sequencing

Treutlein¹,

Gökçe

Quake

et al. 2014

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

298

262

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Neurexins are evolutionarily conserved presynaptic cell-adhesion molecules that are essential for normal synapse formation and synaptic transmission. Indirect evidence has indicated that extensive alternative splicing of neurexin mRNAs may produce hundreds if not thousands of neurexin isoforms, but no direct evidence for such diversity has been available. Here we use unbiased long-read sequencing of full-length neurexin (Nrxn)1α, Nrxn1β, Nrxn2β, Nrxn3α, and Nrxn3β mRNAs to systematically assess how many sites of alternative splicing are used in neurexins with a significant frequency, and whether alternative splicing events at these sites are independent of each other. In sequencing more than 25,000 full-length mRNAs, we identified a novel, abundantly used alternatively spliced exon of Nrxn1α and Nrxn3α (referred to as alternatively spliced sequence 6) that encodes a 9-residue insertion in the flexible hinge region between the fifth LNS (laminin-α, neurexin, sex hormone-binding globulin) domain and the third EGF-like sequence. In addition, we observed several larger-scale events of alternative splicing that deleted multiple domains and were much less frequent than the canonical six sites of alternative splicing in neurexins. All of the six canonical events of alternative splicing appear to be independent of each other, suggesting that neurexins may exhibit an even larger isoform diversity than previously envisioned and comprise thousands of variants. Our data are consistent with the notion that α-neurexins represent extracellular protein-interaction scaffolds in which different LNS and EGF domains mediate distinct interactions that affect diverse functions and are independently regulated by independent events of alternative splicing.N eurons form highly specific and complex patterns of synaptic connections that underlie all brain function (1-5). Such specific connections require trillions of chemically differentiated synapses whose identity may be shaped by interactions of specific pre-and postsynaptic signaling molecules, especially cell-adhesion molecules. The genome size is insufficient to encode such diversity, but a mixture of combinatorial expression patterns that pair different synaptic cell-adhesion molecules with each other and of distinct alternative splicing patterns that amplify the number of cell-adhesion molecules into a large number of isoforms may generate the number of transsynaptic interactions needed to account for the enormous diversity of synaptic connections. In Drosophila melanogaster, alternative splicing of the mRNAs encoding the Down syndrome cell-adhesion molecule can generate nearly 20,000 protein isoforms whose structures specify axon bundling but not synapse formation (6). In mammals, alternative splicing of neurexin and some protocadherin mRNAs can also produce thousands of isoforms, which may at least in the case of neurexins be involved in synapse formation (7-10).Neurexins are type I membrane proteins that were discovered as presynaptic receptors for α-latrotoxin (8, 9). Six prin...

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The Genetic Analysis of Functional Connectomics in Drosophila

Cited by 35 publications

References 286 publications

Monitoring cell-cell contacts in vivo in transgenic animals

Monitoring cell-cell contacts in vivo in transgenic animals

Multiple Redundant Medulla Projection Neurons Mediate Color Vision inDrosophila

Cartography of neurexin alternative splicing mapped by single-molecule long-read mRNA sequencing

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