Synapse maintenance is impacted by ATAT-2 tubulin acetyltransferase activity and the RPM-1 signaling hub
Abstract
Synapse formation is comprised of target recognition, synapse assembly, and synapse maintenance. Maintaining established synaptic connections is essential for generating functional circuitry and synapse instability is a hallmark of neurodegenerative disease. While many molecules impact synapse formation generally, we know little about molecules that affect synapse maintenance in vivo. Using genetics and developmental time course analysis in C. elegans, we show that the a-tubulin acetyltransferase ATAT-2 and the signaling hub RPM-1 are required presynaptically to maintain stable synapses. Importantly, the enzymatic acetyltransferase activity of ATAT-2 is required for synapse maintenance. Our analysis revealed that RPM-1 is a hub in a genetic network composed of ATAT-2, PTRN-1 and DLK-1. In this network, ATAT-2 functions independent of the DLK-1 MAPK and likely acts downstream of RPM-1. Thus, our study reveals an important role for tubulin acetyltransferase activity in presynaptic maintenance, which occurs via the RPM-1/ATAT-2 pathway.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
National Institute of Neurological Disorders and Stroke (R01 NS072129)
- Brock Grill
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Graeme W Davis, University of California, San Francisco, United States
Version history
- Received: November 30, 2018
- Accepted: January 15, 2019
- Accepted Manuscript published: January 17, 2019 (version 1)
- Accepted Manuscript updated: January 18, 2019 (version 2)
- Version of Record published: January 31, 2019 (version 3)
Copyright
© 2019, Borgen 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
-
- 1,729
- views
-
- 244
- downloads
-
- 9
- 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
-
- Developmental Biology
Precise developmental timing control is essential for organism formation and function, but its mechanisms are unclear. In C. elegans, the microRNA lin-4 critically regulates developmental timing by post-transcriptionally downregulating the larval-stage-fate controller LIN-14. However, the mechanisms triggering the activation of lin-4 expression toward the end of the first larval stage remain unknown. We demonstrate that the transmembrane transcription factor MYRF-1 is necessary for lin-4 activation. MYRF-1 is initially localized on the cell membrane, and its increased cleavage and nuclear accumulation coincide with lin-4 expression timing. MYRF-1 regulates lin-4 expression cell-autonomously and hyperactive MYRF-1 can prematurely drive lin-4 expression in embryos and young first-stage larvae. The tandem lin-4 promoter DNA recruits MYRF-1GFP to form visible loci in the nucleus, suggesting that MYRF-1 directly binds to the lin-4 promoter. Our findings identify a crucial link in understanding developmental timing regulation and establish MYRF-1 as a key regulator of lin-4 expression.
-
- Developmental Biology
- Structural Biology and Molecular Biophysics
The receptor tyrosine kinase ROR2 mediates noncanonical WNT5A signaling to orchestrate tissue morphogenetic processes, and dysfunction of the pathway causes Robinow syndrome, brachydactyly B, and metastatic diseases. The domain(s) and mechanisms required for ROR2 function, however, remain unclear. We solved the crystal structure of the extracellular cysteine-rich (CRD) and Kringle (Kr) domains of ROR2 and found that, unlike other CRDs, the ROR2 CRD lacks the signature hydrophobic pocket that binds lipids/lipid-modified proteins, such as WNTs, suggesting a novel mechanism of ligand reception. Functionally, we showed that the ROR2 CRD, but not other domains, is required and minimally sufficient to promote WNT5A signaling, and Robinow mutations in the CRD and the adjacent Kr impair ROR2 secretion and function. Moreover, using function-activating and -perturbing antibodies against the Frizzled (FZ) family of WNT receptors, we demonstrate the involvement of FZ in WNT5A-ROR signaling. Thus, ROR2 acts via its CRD to potentiate the function of a receptor super-complex that includes FZ to transduce WNT5A signals.