Neuregulin-1 Type III Determines the Ensheathment Fate of Axons

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2005 Sep 1

PMID 16129398

Citations 360

Authors

Carla Taveggia

George Zanazzi

Ashley Petrylak

Hiroko Yano

Jack Rosenbluth

Steven Einheber

Xiaorong Xu

Raymond M Esper

Jeffrey A Loeb

Peter Shrager

Moses V Chao

Douglas L Falls

Lorna Role

James L Salzer

Affiliations

Soon will be listed here.

Abstract

The signals that determine whether axons are ensheathed or myelinated by Schwann cells have long been elusive. We now report that threshold levels of neuregulin-1 (NRG1) type III on axons determine their ensheathment fate. Ensheathed axons express low levels whereas myelinated fibers express high levels of NRG1 type III. Sensory neurons from NRG1 type III deficient mice are poorly ensheathed and fail to myelinate; lentiviral-mediated expression of NRG1 type III rescues these defects. Expression also converts the normally unmyelinated axons of sympathetic neurons to myelination. Nerve fibers of mice haploinsufficient for NRG1 type III are disproportionately unmyelinated, aberrantly ensheathed, and hypomyelinated, with reduced conduction velocities. Type III is the sole NRG1 isoform retained at the axon surface and activates PI 3-kinase, which is required for Schwann cell myelination. These results indicate that levels of NRG1 type III, independent of axon diameter, provide a key instructive signal that determines the ensheathment fate of axons.

Citing Articles

Niacin ameliorates Charcot-Marie-Tooth 4B1 neuropathy without interfering with nerve regeneration.

Cipriani S, Porrello E, Cerea M, Gazzaniga A, Di Guardo R, Heslegrave A Brain Commun. 2025; 7(1):fcaf039.

PMID: 39926607 PMC: 11803425. DOI: 10.1093/braincomms/fcaf039.

Developmental axon diameter growth of central nervous system axons does not depend on ensheathment or myelination by oligodendrocytes.

Bin J, Emberley K, Buscham T, Eichel-Vogel M, Doan R, Steyer A bioRxiv. 2025; .

PMID: 39829751 PMC: 11741303. DOI: 10.1101/2025.01.10.632348.

Wallerian degeneration: From mechanism to disease to imaging.

Tian R, Zhou Y, Ren Y, Zhang Y, Tang W Heliyon. 2025; 11(1):e40729.

PMID: 39811315 PMC: 11730939. DOI: 10.1016/j.heliyon.2024.e40729.

Schwann Cells in Neuromuscular Disorders: A Spotlight on Amyotrophic Lateral Sclerosis.

Moss K, Saxena S Cells. 2025; 14(1).

PMID: 39791748 PMC: 11719703. DOI: 10.3390/cells14010047.

Schwann Cell-Specific Ablation of Beclin 1 Impairs Myelination and Leads to Motor and Sensory Neuropathy in Mice.

Gambarotto L, Russo L, Bresolin S, Persano L, DAmore R, Ronchi G Adv Sci (Weinh). 2024; 12(5):e2308965.

PMID: 39680476 PMC: 11792035. DOI: 10.1002/advs.202308965.

References

Esper R, Loeb J . Rapid axoglial signaling mediated by neuregulin and neurotrophic factors. J Neurosci. 2004; 24(27):6218-27. PMC: 6729661. DOI: 10.1523/JNEUROSCI.1692-04.2004. View

Cosgaya J, Chan J, Shooter E . The neurotrophin receptor p75NTR as a positive modulator of myelination. Science. 2002; 298(5596):1245-8. DOI: 10.1126/science.1076595. View

Frenzel K, Falls D . Neuregulin-1 proteins in rat brain and transfected cells are localized to lipid rafts. J Neurochem. 2001; 77(1):1-12. DOI: 10.1046/j.1471-4159.2001.t01-1-00132.x. View

Vabnick I, Trimmer J, Schwarz T, Levinson S, Risal D, Shrager P . Dynamic potassium channel distributions during axonal development prevent aberrant firing patterns. J Neurosci. 1999; 19(2):747-58. PMC: 6782197. View

Marshall C . Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell. 1995; 80(2):179-85. DOI: 10.1016/0092-8674(95)90401-8. View

Roufa D, Bunge M, Johnson M, Cornbrooks C . Variation in content and function of non-neuronal cells in the outgrowth of sympathetic ganglia from embryos of differing age. J Neurosci. 1986; 6(3):790-802. PMC: 6568474. View

Aguayo A, Charron L, Bray G . Potential of Schwann cells from unmyelinated nerves to produce myelin: a quantitative ultrastructural and radiographic study. J Neurocytol. 1976; 5(8):565-73. DOI: 10.1007/BF01175570. View

Hoke A, Ho T, Crawford T, LeBel C, Hilt D, Griffin J . Glial cell line-derived neurotrophic factor alters axon schwann cell units and promotes myelination in unmyelinated nerve fibers. J Neurosci. 2003; 23(2):561-7. PMC: 6741898. View

Melendez-Vasquez C, Einheber S, Salzer J . Rho kinase regulates schwann cell myelination and formation of associated axonal domains. J Neurosci. 2004; 24(16):3953-63. PMC: 6729425. DOI: 10.1523/JNEUROSCI.4920-03.2004. View

10.

Wolpowitz D, Mason T, Dietrich P, Mendelsohn M, Talmage D, Role L . Cysteine-rich domain isoforms of the neuregulin-1 gene are required for maintenance of peripheral synapses. Neuron. 2000; 25(1):79-91. DOI: 10.1016/s0896-6273(00)80873-9. View

11.

Smith K, Blakemore W, Murray J, PATTERSON R . Internodal myelin volume and axon surface area. A relationship determining myelin thickness?. J Neurol Sci. 1982; 55(2):231-46. DOI: 10.1016/0022-510x(82)90103-4. View

12.

Windebank A, Wood P, Bunge R, Dyck P . Myelination determines the caliber of dorsal root ganglion neurons in culture. J Neurosci. 1985; 5(6):1563-9. PMC: 6565257. View

13.

Ho W, Armanini M, Nuijens A, PHILLIPS H, Osheroff P . Sensory and motor neuron-derived factor. A novel heregulin variant highly expressed in sensory and motor neurons. J Biol Chem. 1995; 270(24):14523-32. DOI: 10.1074/jbc.270.24.14523. View

14.

Garratt A, Britsch S, Birchmeier C . Neuregulin, a factor with many functions in the life of a schwann cell. Bioessays. 2000; 22(11):987-96. DOI: 10.1002/1521-1878(200011)22:11<987::AID-BIES5>3.0.CO;2-5. View

15.

Ogata T, Iijima S, Hoshikawa S, Miura T, Yamamoto S, Oda H . Opposing extracellular signal-regulated kinase and Akt pathways control Schwann cell myelination. J Neurosci. 2004; 24(30):6724-32. PMC: 6729716. DOI: 10.1523/JNEUROSCI.5520-03.2004. View

16.

Yang X, Kuo Y, Devay P, Yu C, Role L . A cysteine-rich isoform of neuregulin controls the level of expression of neuronal nicotinic receptor channels during synaptogenesis. Neuron. 1998; 20(2):255-70. DOI: 10.1016/s0896-6273(00)80454-7. View

17.

Einheber S, Zanazzi G, Ching W, Scherer S, Milner T, Peles E . The axonal membrane protein Caspr, a homologue of neurexin IV, is a component of the septate-like paranodal junctions that assemble during myelination. J Cell Biol. 1998; 139(6):1495-506. PMC: 2132621. DOI: 10.1083/jcb.139.6.1495. View

18.

Nagata-Ohashi K, Ohta Y, Goto K, Chiba S, Mori R, Nishita M . A pathway of neuregulin-induced activation of cofilin-phosphatase Slingshot and cofilin in lamellipodia. J Cell Biol. 2004; 165(4):465-71. PMC: 2172350. DOI: 10.1083/jcb.200401136. View

19.

Haney C, Sahenk Z, Li C, Lemmon V, Roder J, Trapp B . Heterophilic binding of L1 on unmyelinated sensory axons mediates Schwann cell adhesion and is required for axonal survival. J Cell Biol. 1999; 146(5):1173-84. PMC: 2169489. DOI: 10.1083/jcb.146.5.1173. View

20.

FRIEDE R . Control of myelin formation by axon caliber (with a model of the control mechanism). J Comp Neurol. 1972; 144(2):233-52. DOI: 10.1002/cne.901440207. View