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Significance Statement
Tyro3 receptor is the potential drug target for demyelinating diseases. Tyro3 knockout mice display reduced myelin thickness. We also find that knockout mice of Fyn nonreceptor tyrosine kinase, an effector kinase of the Tyro3 receptor, exhibit decreased myelin thickness. Thus, the Tyro3 and Fyn signaling unit is required for proper myelination, illustrating that they are new drug targets for demyelinating diseases as well as for nerve regeneration after injury.
Figure legend: Left panel indicates an electron micrographic photograph of the wild type mouse peripheral nerve (cross section; 1000-fold magnification). Right one does that of the Tyro3 knockout mouse nerve (the same magnification). The scale bar indicates 5 micrometers.
Journal Reference
Mol Biol Cell. 2015 Oct 1;26(19):3489-503.
Miyamoto Y1, Torii T1, Takada S2, Ohno N3, Saitoh Y3, Nakamura K1, Ito A4, Ogata T5, Terada N6, Tanoue A1, Yamauchi J7.
[expand title=”Show Affiliations”]- Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
- Department of Systems BioMedicine, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
- Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan.
- Research Center, Nissei Bilis, Koga, Shiga 528-0052, Japan.
- Department of Rehabilitation for the Movement Functions, National Rehabilitation Center for Persons with Disabilities Research Institute, Tokorozawa, Saitama 359-8555, Japan.
- Graduate School of Medicine, Shinshu University, Matsumoto, Nagano 390-8621, Japan.
- Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8510, Japan [email protected]).
Abstract
During early development of the peripheral nervous system, Schwann cell precursors proliferate, migrate, and differentiate into premyelinating Schwann cells. After birth, Schwann cells envelop neuronal axons with myelin sheaths. Although some molecular mechanisms underlying myelination by Schwann cells have been identified, the whole picture remains unclear. Here we show that signaling through Tyro3 receptor tyrosine kinase and its binding partner, Fyn nonreceptor cytoplasmic tyrosine kinase, is involved in myelination by Schwann cells. Impaired formation of myelin segments is observed in Schwann cell neuronal cultures established from Tyro3-knockout mouse dorsal root ganglia (DRG). Indeed, Tyro3-knockout mice exhibit reduced myelin thickness. By affinity chromatography, Fyn was identified as the binding partner of the Tyro3 intracellular domain, and activity of Fyn is down-regulated in Tyro3-knockout mice, suggesting that Tyro3, acting through Fyn, regulates myelination. Ablating Fyn in mice results in reduced myelin thickness. Decreased myelin formation is observed in cultures established from Fyn-knockout mouse DRG. Furthermore, decreased kinase activity levels and altered expression of myelination-associated transcription factors are observed in these knockout mice. These results suggest the involvement of Tyro3 receptor and its binding partner Fyn in Schwann cell myelination. This constitutes a newly recognized receptor-linked signaling mechanism that can control Schwann cell myelination.
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