Involvement of the Tyro3 receptor and its intracellular partner Fyn signaling in Schwann cell myelination

Figure Legend: Mitochondria harboring spastic paraplegia (SPG) 13-associated mutations are co-localized with cleaved (active) caspase 3. Two amino acid mutations Val-98-to-Ile (V98I, upper panels) and Gln-461-to-Glu (Q461E, lower panels) of mitochondrial heat shock protein HSPD1 are associated with SPG13, triggering an apoptotic molecular cascade. Green and red colors indicate mutant HSPD1 and cleaved caspase 3.

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”]

1. Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
2. Department of Systems BioMedicine, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
3. Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan.
4. Research Center, Nissei Bilis, Koga, Shiga 528-0052, Japan.
5. Department of Rehabilitation for the Movement Functions, National Rehabilitation Center for Persons with Disabilities Research Institute, Tokorozawa, Saitama 359-8555, Japan.
6. Graduate School of Medicine, Shinshu University, Matsumoto, Nagano 390-8621, Japan.
7. 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:  [email protected]).

[/expand]

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.

© 2015 Miyamoto et al. This article is distributed by The American Society for Cell Biology under license from the author(s).

Go To Mol Biol Cell