Activity-dependent modulation of synapse-regulating genes in astrocytes
- Salk Institute for Biological Studies, United States
- Thomas Jefferson University, United States
- Sanford Burnham Prebys Medical Discovery Institute, United States
- The Salk Institute for Biological Studies, United States
- Howard Hughes Medical Institute, Salk Institute for Biological Studies, United States
Abstract
Astrocytes regulate the formation and function of neuronal synapses via multiple signals, however, what controls regional and temporal expression of these signals during development is unknown. We determined the expression profile of astrocyte synapse-regulating genes in the developing mouse visual cortex, identifying astrocyte signals that show differential temporal and layer-enriched expression. These patterns are not intrinsic to astrocytes, but regulated by visually-evoked neuronal activity, as they are absent in mice lacking glutamate release from thalamocortical terminals. Consequently, synapses remain immature. Expression of synapse-regulating genes and synaptic development are also altered when astrocyte signaling is blunted by diminishing calcium release from astrocyte stores. Single nucleus RNA sequencing identified groups of astrocytic genes regulated by neuronal and astrocyte activity, and a cassette of genes that show layer-specific enrichment. Thus, the development of cortical circuits requires coordinated signaling between astrocytes and neurons, highlighting astrocytes as a target to manipulate in neurodevelopmental disorders.
Data availability
DATA AVAILABILITYAll data supporting the results of this study can be found in the following locations:Processed RNA sequencing data presented in Figure 1 is available in Figure 1- Source Data 1.Data presented in graphs in Figures 2-5 is available in Figure 2-5 Source Data files.Processed single nucleus RNA sequencing data presented in Figure 6 is available in Figure 6-Source Data 1.The RNA sequencing data has been deposited at GEO. Ribotag data is available at GSE161398 and glial snRNAseq at GSE163775.Processed RNA sequencing data is available in a searchable format at the following web locations:Ribotag astrocyte developmental dataset:igc1.salk.edu:3838/astrocyte_transcriptomeSingle nucleus glial cell sequencing:mouse-astro-dev.cells.ucsc.edu
-
Astrocyte developmental transcriptome from mouse visual cortexNCBI Gene Expression Omnibus, GSE161398.
-
Activity-dependent modulation of synapse-regulating genes in astrocytesNCBI Gene Expression Omnibus, GSE163775.
-
Astrocyte-enriched pan-brain aging transcriptomeNCBI Gene Expression Omnibus, GSE99791.
Article and author information
Author details
Isabella Farhy-Tselnicker
Elena Blanco-Suarez
Funding
National Institutes of Health (NS105742)
- Nicola J Allen
National Institutes of Health (NS089791)
- Nicola J Allen
Pew Charitable Trusts
- Nicola J Allen
Chan Zuckerberg Initiative (2018-191894)
- Nicola J Allen
Howard Hughes Medical Institute
- Joseph R Ecker
National Institutes of Health (NIH NCI CCSG P30 014195)
- Maxim N Shokhirev
Hearst Foundations
- Nicola J Allen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Beth Stevens, Boston Children's Hospital, United States
Ethics
Animal experimentation: This study was performed in accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animal work was approved by the Salk Institute Institutional Animal Care and Use Committee (IACUC) protocol 12-00023.
Version history
- Preprint posted: December 30, 2020 (view preprint)
- Received: May 19, 2021
- Accepted: September 7, 2021
- Accepted Manuscript published: September 8, 2021 (version 1)
- Version of Record published: October 7, 2021 (version 2)
Copyright
© 2021, Farhy-Tselnicker 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
-
- 7,601
- views
-
- 995
- downloads
-
- 58
- 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)
Activity-dependent modulation of synapse-regulating genes in astrocytes
eLife 10:e70514.
https://doi.org/10.7554/eLife.70514
Further reading
-
- Developmental Biology
Vascular smooth muscle cells (VSMCs) envelop vertebrate brain arteries and play a crucial role in regulating cerebral blood flow and neurovascular coupling. The dedifferentiation of VSMCs is implicated in cerebrovascular disease and neurodegeneration. Despite its importance, the process of VSMC differentiation on brain arteries during development remains inadequately characterized. Understanding this process could aid in reprogramming and regenerating dedifferentiated VSMCs in cerebrovascular diseases. In this study, we investigated VSMC differentiation on zebrafish circle of Willis (CoW), comprising major arteries that supply blood to the vertebrate brain. We observed that arterial specification of CoW endothelial cells (ECs) occurs after their migration from cranial venous plexus to form CoW arteries. Subsequently, acta2+ VSMCs differentiate from pdgfrb+ mural cell progenitors after they were recruited to CoW arteries. The progression of VSMC differentiation exhibits a spatiotemporal pattern, advancing from anterior to posterior CoW arteries. Analysis of blood flow suggests that earlier VSMC differentiation in anterior CoW arteries correlates with higher red blood cell velocity and wall shear stress. Furthermore, pulsatile flow induces differentiation of human brain PDGFRB+ mural cells into VSMCs, and blood flow is required for VSMC differentiation on zebrafish CoW arteries. Consistently, flow-responsive transcription factor klf2a is activated in ECs of CoW arteries prior to VSMC differentiation, and klf2a knockdown delays VSMC differentiation on anterior CoW arteries. In summary, our findings highlight blood flow activation of endothelial klf2a as a mechanism regulating initial VSMC differentiation on vertebrate brain arteries.
-
- 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.
