Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in C. elegans
- University of Massachusetts Medical School, United States
- Mount Sinai Hospital, Canada
- The Rockefeller University, United States
Abstract
Mutations in pre-synaptic voltage gated calcium channels can lead to familial hemiplegic migraine type 1 (FHM1). While mammalian studies indicate that the migraine brain is hyperexcitable due to enhanced excitation or reduced inhibition, the molecular and cellular mechanisms underlying this excitatory/inhibitory (E/I) imbalance are poorly understood. We identified a gain-of-function (gf) mutation in the Caenorhabditis elegans CaV2 channel α1 subunit, UNC-2, which leads to increased calcium currents. unc-2(zf35gf) mutants exhibit hyperactivity and seizure-like motor behaviors. Expression of the unc-2 gene with FHM1 substitutions R192Q and S218L leads to hyperactivity similar to that of unc-2(zf35gf) mutants. unc-2(zf35gf) mutants display increased cholinergic- and decreased GABAergic-transmission. Moreover, increased cholinergic transmission in unc-2(zf35gf) mutants leads to an increase of cholinergic synapses and a TAX-6/calcineurin dependent reduction of GABA synapses. Our studies reveal mechanisms through which CaV2 gain-of-function mutations disrupt excitation-inhibition balance in the nervous system.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures.
Article and author information
Author details
Funding
National Institutes of Health (GM084491)
- Mark J Alkema
National Institutes of Health (NS082525)
- Mei Zhen
- Mark J Alkema
Canadian Institutes of Health Research (154274)
- Mei Zhen
Natural Sciences and Engineering Research Council of Canada (RGPIN-2017-06738)
- Mei Zhen
National Natural Science Foundation of China (31671052)
- Shangbang Gao
National Institutes of Health (NS064263)
- Michael M Francis
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2019, Huang 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
-
- 3,550
- views
-
- 444
- downloads
-
- 39
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
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)
Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in C. elegans
eLife 8:e45905.
https://doi.org/10.7554/eLife.45905
Further reading
-
- Cancer Biology
- Genetics and Genomics
Interpretation of variants identified during genetic testing is a significant clinical challenge. In this study, we developed a high-throughput CDKN2A functional assay and characterized all possible human CDKN2A missense variants. We found that 17.7% of all missense variants were functionally deleterious. We also used our functional classifications to assess the performance of in silico models that predict the effect of variants, including recently reported models based on machine learning. Notably, we found that all in silico models performed similarly when compared to our functional classifications with accuracies of 39.5–85.4%. Furthermore, while we found that functionally deleterious variants were enriched within ankyrin repeats, we did not identify any residues where all missense variants were functionally deleterious. Our functional classifications are a resource to aid the interpretation of CDKN2A variants and have important implications for the application of variant interpretation guidelines, particularly the use of in silico models for clinical variant interpretation.
-
- Genetics and Genomics
In mammals, spermatogonial cells (SPGs) are undifferentiated male germ cells in testis that are quiescent until birth and then self-renew and differentiate to produce spermatogenic cells and functional sperm from early postnatal life throughout adulthood. The transcriptome of SPGs is highly dynamic and timely regulated during postnatal development. We examined if such dynamics involves changes in chromatin organization by profiling the transcriptome and chromatin accessibility of SPGs from early postnatal stages to adulthood in mice using deep RNA-seq, ATAC-seq and computational deconvolution analyses. By integrating transcriptomic and epigenomic features, we show that SPGs undergo massive chromatin remodeling during postnatal development that partially correlates with distinct gene expression profiles and transcription factors (TF) motif enrichment. We identify genomic regions with significantly different chromatin accessibility in adult SPGs that are marked by histone modifications associated with enhancers and promoters. Some of the regions with increased accessibility correspond to transposable element subtypes enriched in multiple TFs motifs and close to differentially expressed genes. Our results underscore the dynamics of chromatin organization in developing germ cells and complement existing datasets on SPGs by providing maps of the regulatory genome at high resolution from the same cell populations at early postnatal, late postnatal and adult stages collected from single individuals.
