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Differential Effects of Human L1CAM Mutations on Complementing Guidance and Synaptic Defects in Drosophila melanogaster
Title
Differential Effects of Human L1CAM Mutations on Complementing Guidance and Synaptic Defects in Drosophila melanogaster.
Creator
Kudumala, Sirisha, Freund, Julie, Hortsch, Michael, Godenschwege, Tanja A., Labrador, Juan-Pablo
Abstract/Description
A large number of different pathological L1CAM mutations have been identified that result in a broad spectrum of neurological and non-neurological phenotypes. While many of these mutations have been characterized for their effects on homophilic and heterophilic interactions, as well as expression levels in vitro, there are only few studies on their biological consequences in vivo. The single L1-type CAM gene in Drosophila, neuroglian (nrg), has distinct functions during axon guidance and...
Show moreA large number of different pathological L1CAM mutations have been identified that result in a broad spectrum of neurological and non-neurological phenotypes. While many of these mutations have been characterized for their effects on homophilic and heterophilic interactions, as well as expression levels in vitro, there are only few studies on their biological consequences in vivo. The single L1-type CAM gene in Drosophila, neuroglian (nrg), has distinct functions during axon guidance and synapse formation and the phenotypes of nrg mutants can be rescued by the expression of human L1CAM. We previously showed that the highly conserved intracellular FIGQY Ankyrin-binding motif is required for L1CAM-mediated synapse formation, but not for neurite outgrowth or axon guidance of the Drosophila giant fiber (GF) neuron. Here, we use the GF as a model neuron to characterize the pathogenic L120V, Y1070C, C264Y, H210Q, E309K and R184Q extracellular L1CAM missense mutations and a L1CAM protein with a disrupted ezrin–moesin–radixin (ERM) binding site to investigate the signaling requirements for neuronal development. We report that different L1CAM mutations have distinct effects on axon guidance and synapse formation. Furthermore, L1CAM homophilic binding and signaling via the ERM motif is essential for axon guidance in Drosophila. In addition, the human pathological H210Q, R184Q and Y1070C, but not the E309K and L120V L1CAM mutations affect outside-in signaling via the FIGQY Ankyrin binding domain which is required for synapse formation. Thus, the pathological phenotypes observed in humans are likely to be caused by the disruption of signaling required for both, guidance and synaptogenesis.
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Date Issued
2013-10-14
PURL
http://purl.flvc.org/fau/fd/FAUIR000080
Format
Citation
New Tools for Targeted Disruption of Cholinergic Synaptic Transmission in Drosophila melanogaster
Title
New Tools for Targeted Disruption of Cholinergic Synaptic Transmission in Drosophila melanogaster.
Creator
Mejia, Monica, Heghinian, Mari D., Mari, Frank, Godenschwege, Tanja A., McCabe, Brian D.
Abstract/Description
Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels. The a7 subtype of nAChRs is involved in neurological pathologies such as Parkinson’s disease, Alzheimer’s disease, addiction, epilepsy and autism spectrum disorders. The Drosophila melanogaster a7 (Da7) has the closest sequence homology to the vertebrate a7 subunit and it can form homopentameric receptors just as the vertebrate counterpart. The Da7 subunits are essential for the function of the Giant Fiber...
Show moreNicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels. The a7 subtype of nAChRs is involved in neurological pathologies such as Parkinson’s disease, Alzheimer’s disease, addiction, epilepsy and autism spectrum disorders. The Drosophila melanogaster a7 (Da7) has the closest sequence homology to the vertebrate a7 subunit and it can form homopentameric receptors just as the vertebrate counterpart. The Da7 subunits are essential for the function of the Giant Fiber circuit, which mediates the escape response of the fly. To further characterize the receptor function, we generated different missense mutations in the Da7 nAChR’s ligand binding domain. We characterized the effects of targeted expression of two UAS-constructs carrying a single mutation, D197A and Y195T, as well as a UAS-construct carrying a triple D77T, L117Q, I196P mutation in a Da7 null mutant and in a wild type background. Expression of the triple mutation was able to restore the function of the circuit in Da7 null mutants and had no disruptive effects when expressed in wild type. In contrast, both single mutations severely disrupted the synaptic transmission of Da7-dependent but not glutamatergic or gap junction dependent synapses in wild type background, and did not or only partially rescued the synaptic defects of the null mutant. These observations are consistent with the formation of hybrid receptors, consisting of D197A or Y195T subunits and wild type Da7 subunits, in which the binding of acetylcholine or acetylcholine-induced conformational changes of the Da7 receptor are altered and causes inhibition of cholinergic responses. Thus targeted expression of D197A or Y195T can be used to selectively disrupt synaptic transmission of Da7-dependent synapses in neuronal circuits. Hence, these constructs can be used as tools to study learning and memory or addiction associated behaviors by allowing the manipulation of neuronal processing in the circuits without affecting other cellular signaling.
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Date Issued
2013-05-30
PURL
http://purl.flvc.org/fau/fd/FAUIR000083
Format
Citation
Transsynaptic Coordination of Synaptic Growth, Function, and Stability by the L1-Type CAM Neuroglian
Title
Transsynaptic Coordination of Synaptic Growth, Function, and Stability by the L1-Type CAM Neuroglian.
Creator
Enneking, Eva-Maria, Kudumala, Sirisha R., Moreno, Eliza, Stephan, Raiko, Boerner, Jana, Godenschwege, Tanja A., Pielage, Jan, Bellen, Hugo J.
Date Issued
2013-04-16
PURL
http://purl.flvc.org/fau/fd/FAUIR000106
Format
Citation