Schwann cell-specific PTEN and EGFR dysfunctions affect neuromuscular junction development by impairing Agrin signaling and autophagy
Open accessAbstract
The neuromuscular junction (NMJ) is formed by motor nerve terminals, post-junctional muscle membranes, and terminal Schwann cells (SCs). The formation of NMJ requires complex and dynamic molecular interactions. Nerve- and muscle-derived molecules have been well characterized but the mechanistic involvement of SC in NMJ development remains poorly understood. SC-specific phosphatase and tensin homolog (Pten) inactivation and epidermal growth factor receptor (EGFR) overexpression (Dhh-Cre; Cnp-EGFR; Pten flox/flox or DET) mice were used and NMJ malformation was observed in these mice. Acetylcholine receptors (AChRs) were distorted and varicose presynaptic nerve terminals appeared in the tibialis anterior (TA) muscle of DET mice. Agrin signaling related to NMJ development, was downregulated in TA muscle. Both RAS/MEK/ERK and PI3K/AKT/mTOR signaling pathways were activated in the sciatic nerves of DET mice. In addition, autophagy was downregulated in these sciatic nerves. Interestingly, the use of Torin 2, an mTOR inhibitor, rescued the phenotype. The downregulated-autophagy might account for Agrin signaling abnormity, which induced NMJ malformation. Taken together, our results indicate that SCs-specific Pten and EGFR cooperation are essential for NMJ development.
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Schwann cell-specific PTEN deletion or EGFR overexpression attenuate peripheral nerve autophagy and lead to disorganization of the nascent neuromuscular junction.
“Additional non-cell autonomous effects are observed with Schwann cell-specific PTEN deletion or EGFR overexpression, which attenuate peripheral nerve autophagy and lead to disorganization of the nascent neuromuscular junction [461].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [461]
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Autophagy and ALS: mechanistic insights and therapeutic implications
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- Authors
- Zhang, S.-J., Li, X.-X., Yu, Y., Chiu, A. P., Lo, L. H., To, J. C., Rowlands, D. K., & Keng, V. W.
- Affiliations
- Guangzhou University of Chinese Medicine (CN)
- Hong Kong Polytechnic University (HK)
- Chinese University of Hong Kong (HK)
- Corresponding author
- Keng, Vincent W.
- ORCID
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 515
- Issue
- 1
- Pages
- 50-56
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2946142499
- Cited by
- 13
- References
- 40
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 4 · 2020: 1 · 2019: 1
- FWCI
- 0.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- PolyU Institutional Research Archive (Hong Kong Polytechnic University) (submittedVersion, cc-by-nc-nd)
- Funders
- Research Grants Council Collaborative Research Fund Scheme (C5012-15E)
- Hong Kong SAR Government
- Department of Applied Biology and Chemical Technology
- The Hong Kong Polytechnic University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
- Keywords
- neuromuscular junction formation, Schwann cells, PTEN, EGFR, autophagy, mTOR signaling, Ras/MEK/ERK pathway, PI3K/Akt signaling, acetylcholine receptor, presynaptic terminals, terminal Schwann cells
- MeSH terms
- Animals, Autophagy, Female, Male, Naphthyridines, Neuromuscular Junction, Receptors, Cholinergic, Schwann Cells, Sciatic Nerve, Signal Transduction, Presynaptic Terminals, Agrin, Muscle, Skeletal, MAP Kinase Signaling System, PTEN Phosphohydrolase, Mice, TOR Serine-Threonine Kinases, ErbB Receptors
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