A genetic basis for molecular asymmetry at vertebrate electrical synapses
Abstract
Neural network function is based upon the patterns and types of connections made between neurons. Neuronal synapses are adhesions specialized for communication and they come in two types, chemical and electrical. Communication at chemical synapses occurs via neurotransmitter release whereas electrical synapses utilize gap junctions for direct ionic and metabolic coupling. Electrical synapses are often viewed as symmetrical structures, with the same components making both sides of the gap junction. By contrast, we show that a broad set of electrical synapses in zebrafish, Danio rerio, require two gap-junction-forming Connexins for formation and function. We find that one Connexin functions presynaptically while the other functions postsynaptically in forming the channels. We also show that these synapses are required for the speed and coordination of escape responses. Our data identify a genetic basis for molecular asymmetry at vertebrate electrical synapses and show they are required for appropriate behavioral performance.
Data availability
-
Dis2 RNA-seq wildtype and mutantPublicly available at the NCBI Sequence Read Archive (accession no: PRJNA172016).
Article and author information
Author details
Funding
National Institute of Neurological Disorders and Stroke (F32NS074839)
- Adam C Miller
National Institute of Mental Health (R01MH109498)
- Michael Granato
National Eye Institute (R01EY012857)
- John O'Brien
Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD076585)
- Cecilia B Moens
National Institute of Neurological Disorders and Stroke (R21NS076950)
- Cecilia B Moens
National Institute of Neurological Disorders and Stroke (K99/R00NS085035)
- Adam C Miller
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animals were raised in an Institutional Animal Care and Use Committee (IACUC)-approvedfacility at the Fred Hutchinson Cancer Research Center (Study ID 50552, Submittal ID 7237, IRO #1392).
Copyright
© 2017, Miller et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,160
- views
-
- 423
- downloads
-
- 44
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Biochemistry and Chemical Biology
- Neuroscience
As the world population ages, new molecular targets in aging and Alzheimer’s disease (AD) are needed to combat the expected influx of new AD cases. Until now, the role of RNA structure in aging and neurodegeneration has largely remained unexplored. In this study, we examined human hippocampal postmortem tissue for the formation of RNA G-quadruplexes (rG4s) in aging and AD. We found that rG4 immunostaining strongly increased in the hippocampus with both age and with AD severity. We further found that neurons with the accumulation of phospho-tau immunostaining contained rG4s, rG4 structure can drive tau aggregation, and rG4 staining density depended on APOE genotype in the human tissue examined. Combined with previous studies showing the dependence of rG4 structure on stress and the extreme power of rG4s at oligomerizing proteins, we propose a model of neurodegeneration in which chronic rG4 formation is linked to proteostasis collapse. These morphological findings suggest that further investigation of RNA structure in neurodegeneration is a critical avenue for future treatments and diagnoses.
-
- Neuroscience
- Stem Cells and Regenerative Medicine
Sensory dorsal root ganglion (DRG) neurons have a unique pseudo-unipolar morphology in which a stem axon bifurcates into a peripheral and a central axon, with different regenerative abilities. Whereas peripheral DRG axons regenerate, central axons are unable to regrow. Central axon regeneration can however be elicited by a prior conditioning lesion to the peripheral axon. How DRG axon asymmetry is established remains unknown. Here we developed a rodent in vitro system replicating DRG pseudo-unipolarization and asymmetric axon regeneration. Using this model, we observed that from early development, central DRG axons have a higher density of growing microtubules. This asymmetry was also present in vivo and was abolished by a conditioning lesion that decreased microtubule polymerization of central DRG axons. An axon-specific microtubule-associated protein (MAP) signature, including the severases spastin and katanin and the microtubule regulators CRMP5 and tau, was found and shown to adapt upon conditioning lesion. Supporting its significance, interfering with the DRG MAP signature either in vitro or in vivo readily abolished central-peripheral asymmetries in microtubule dynamics and regenerative ability. In summary, our data unveil that axon-specific microtubule regulation drives asymmetric regeneration of sensory neuron axons.