Gab1 mediates PDGF signaling and is essential to oligodendrocyte differentiation and CNS myelination
Abstract
Oligodendrocytes (OLs) myelinate axons and provide electrical insulation and trophic support for neurons in the central nervous system (CNS). Platelet-derived growth factor (PDGF) is critical for steady-state number and differentiation of oligodendrocyte precursor cells (OPCs), but its downstream targets are unclear. Here, we show for the first time that Gab1, an adaptor protein of receptor tyrosine kinase, is specifically expressed in OL lineage cells and is an essential effector of PDGF signaling in OPCs in mice. Gab1 is down-regulated by PDGF stimulation and up-regulated during OPC differentiation. Conditional deletions of Gab1 in OLs cause CNS hypomyelination by affecting OPC differentiation. Moreover, Gab1 binds to downstream GSK3β and regulated its activity, and thereby affects the nuclear accumulation of β-catenin and the expression of a number of transcription factors critical to myelination. Our work uncovers a novel downstream target of PDGF signaling, which is essential to OPC differentiation and CNS myelination.
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
Ministry of Science and Technology of the People's Republic of China (2017YFA0104200)
- Ying Shen
National Natural Science Foundation of China (31571051)
- Liang Zhou
National Natural Science Foundation of China (81625006)
- Ying Shen
National Natural Science Foundation of China (31820103005)
- Ying Shen
Natural Science Foundation of Zhejiang Province (Z15C090001)
- Ying Shen
Natural Science Foundation of Zhejiang Province (LQ17C090001)
- Na Wang
Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2017PT31038)
- Ying Shen
Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2018PT31041)
- Ying Shen
Chinese Ministry of Education Project 111 Program (B13026)
- Ying Shen
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 of the animals were handled according to approved protocol (ZJU20160019) of the Animal Experimentation Ethics Committee of Zhejiang University.
Copyright
© 2020, Zhou 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
-
- 1,984
- views
-
- 333
- downloads
-
- 18
- 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
-
- Neuroscience
By exposing genes associated with disease, genomic studies provide hundreds of starting points that should lead to druggable processes. However, our ability to systematically translate these genomic findings into biological pathways remains limited. Here, we combine rapid loss-of-function mutagenesis of Alzheimer’s risk genes and behavioural pharmacology in zebrafish to predict disrupted processes and candidate therapeutics. FramebyFrame, our expanded package for the analysis of larval behaviours, revealed that decreased night-time sleep was common to F0 knockouts of all four late-onset Alzheimer’s risk genes tested. We developed an online tool, ZOLTAR, which compares any behavioural fingerprint to a library of fingerprints from larvae treated with 3677 compounds. ZOLTAR successfully predicted that sorl1 mutants have disrupted serotonin signalling and identified betamethasone as a drug which normalises the excessive day-time sleep of presenilin-2 knockout larvae with minimal side effects. Predictive behavioural pharmacology offers a general framework to rapidly link disease-associated genes to druggable pathways.
-
- Neuroscience
Sleep loss increases AMPA-synaptic strength and number in the neocortex. However, this is only part of the synaptic sleep loss response. We report an increased AMPA/NMDA EPSC ratio in frontal-cortical pyramidal neurons of layers 2–3. Silent synapses are absent, decreasing the plastic potential to convert silent NMDA to active AMPA synapses. These sleep loss changes are recovered by sleep. Sleep genes are enriched for synaptic shaping cellular components controlling glutamate synapse phenotype, overlap with autism risk genes, and are primarily observed in excitatory pyramidal neurons projecting intra-telencephalically. These genes are enriched with genes controlled by the transcription factor, MEF2c, and its repressor, HDAC4. Sleep genes can thus provide a framework within which motor learning and training occur mediated by the sleep-dependent oscillation of glutamate-synaptic phenotypes.