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110


Independent anterograde transport and retrograde cotransport of domain components of myelinated axons

Bekku, Yoko; Salzer, James L
Neurons are highly polarized cells organized into functionally and molecularly distinct domains. A key question is whether the multiprotein complexes that comprise these domains are preassembled, transported, and inserted as a complex or whether their components are transported independently and assemble locally. Here, we have dynamically imaged, in pairwise combinations, the vesicular transport of fluorescently tagged components of the nodes of Ranvier and other myelinated axonal domains in sensory neurons cultured alone or together with Schwann cells at the onset of myelination. In general, most proteins are transported independently in the anterograde direction. In contrast, there is substantial cotransport of proteins from distinct domains in the retrograde direction likely due to coendocytosis along the axon. Early myelination did not substantially change these patterns of transport, although it increased the overall numbers of axonal transport vesicles. Our results indicate domain components are transported in separate vesicles for local assembly, not as preformed complexes, and implicate endocytosis along axons as a mechanism of clearance.
PMID: 32289157
ISSN: 1540-8140
CID: 4383392

An unfolding role for ankyrin-G at the axon initial segment

Salzer, James L
PMID: 31501326
ISSN: 1091-6490
CID: 4087682

Necl-4/Cadm4 recruits Par-3 to the Schwann cell adaxonal membrane

Meng, Xiaosong; Maurel, Patrice; Lam, Isabel; Heffernan, Corey; Stiffler, Michael A; McBeath, Gavin; Salzer, James L
Interactions between axons and Schwann cells are essential for the acquisition of Schwann cell radial and longitudinal polarity and myelin sheath assembly. In the internode, the largest of these longitudinal domains, axon-Schwann cell interactions are mediated by the Nectin-like (Necl) cell adhesion proteins, also known as SynCAMs or Cadms. In particular, Necl-1/Cadm3 expressed on the axon surface binds to Necl-4/Cadm4 expressed along the adaxonal membrane of myelinating Schwann cells. Necl-4 promotes myelination in vitro and is required for the timely onset of myelination and the fidelity of the organization of the myelin sheath and the internode in vivo. A key question is the identity of the downstream effectors of Necl-4 that mediate its effects. The cytoplasmic terminal region (CTR) of Necl-4 contains a PDZ-domain binding motif. Accordingly, we used the CTR of Necl-4 in an unbiased proteomic screen of PDZ-domain proteins. We identify Par-3, a multi-PDZ domain containing protein of the Par-aPKC polarity complex previously implicated in myelination, as an interacting protein. Necl-4 and Par-3 are colocalized along the inner Schwann cell membrane and coprecipitate from Schwann cell lysates. The CTR of Necl-4 binds to the first PDZ domain of Par-3 thereby recruiting Par-3 to sites of Necl-4/Necl-1 interaction. Knockdown of Necl-4 perturbs Par-3 localization to the inner membrane of Schwann cells in myelinating co-cultures. These findings implicate interactions of Necl-1/Necl-4 in the recruitment of Par-3 to the Schwann cell adaxonal membrane and the establishment of Schwann cell radial polarity.
PMID: 30585357
ISSN: 1098-1136
CID: 3560382

Schwann cell-derived desert hedgehog regulates the endoneurial fibroblast phenotype in peripheral nerves via Gli1 [Meeting Abstract]

Zotter, Brendan; Samanta, Jayshree; Baloui, Hasna; Salzer, James
ISI:000452787700319
ISSN: 1085-9489
CID: 3557742

Localized Myosin II Activity Regulates Assembly and Plasticity of the Axon Initial Segment

Berger, Stephen L; Leo-Macias, Alejandra; Yuen, Stephanie; Khatri, Latika; Pfennig, Sylvia; Zhang, Yanqing; Agullo-Pascual, Esperanza; Caillol, Ghislaine; Zhu, Min-Sheng; Rothenberg, Eli; Melendez-Vasquez, Carmen V; Delmar, Mario; Leterrier, Christophe; Salzer, James L
The axon initial segment (AIS) is the site of action potential generation and a locus of activity-dependent homeostatic plasticity. A multimeric complex of sodium channels, linked via a cytoskeletal scaffold of ankyrin G and beta IV spectrin to submembranous actin rings, mediates these functions. The mechanisms that specify the AIS complex to the proximal axon and underlie its plasticity remain poorly understood. Here we show phosphorylated myosin light chain (pMLC), an activator of contractile myosin II, is highly enriched in the assembling and mature AIS, where it associates with actin rings. MLC phosphorylation and myosin II contractile activity are required for AIS assembly, and they regulate the distribution of AIS components along the axon. pMLC is rapidly lost during depolarization, destabilizing actin and thereby providing a mechanism for activity-dependent structural plasticity of the AIS. Together, these results identify pMLC/myosin II activity as a common link between AIS assembly and plasticity.
PMCID:5805619
PMID: 29395909
ISSN: 1097-4199
CID: 2947452

Myelination

Salzer, J L; Zalc, B
Myelin is a key evolutionary acquisition that underlay the development of the large, complex nervous systems of all hinged-jaw vertebrates. By promoting rapid, efficient nerve conduction, myelination also made possible the development of the large body size of these vertebrates. In addition to increasing the speed of nerve conduction, myelination has emerged as a source of plasticity in neural circuits that is crucial for proper timing and function. Here, we briefly describe the organization of myelin and of myelinated axons, as well as the functions of myelin in nerve conduction and neural circuits, and consider its potential evolutionary origins.
PMID: 27780071
ISSN: 1879-0445
CID: 2287662

Akt Regulates Axon Wrapping and Myelin Sheath Thickness in the PNS

Domenech-Estevez, Enric; Baloui, Hasna; Meng, Xiaosong; Zhang, Yanqing; Deinhardt, Katrin; Dupree, Jeff L; Einheber, Steven; Chrast, Roman; Salzer, James L
The signaling pathways that regulate myelination in the PNS remain poorly understood. Phosphatidylinositol-4,5-bisphosphate 3-kinase 1A, activated in Schwann cells by neuregulin and the extracellular matrix, has an essential role in the early events of myelination. Akt/PKB, a key effector of phosphatidylinositol-4,5-bisphosphate 3-kinase 1A, was previously implicated in CNS, but not PNS myelination. Here we demonstrate that Akt plays a crucial role in axon ensheathment and in the regulation of myelin sheath thickness in the PNS. Pharmacological inhibition of Akt in DRG neuron-Schwann cell cocultures dramatically decreased MBP and P0 levels and myelin sheath formation without affecting expression of Krox20/Egr2, a key transcriptional regulator of myelination. Conversely, expression of an activated form of Akt in purified Schwann cells increased expression of myelin proteins, but not Krox20/Egr2, and the levels of activated Rac1. Transgenic mice expressing a membrane-targeted, activated form of Akt under control of the 2',3'-cyclic nucleotide 3'-phosphodiesterase promoter, exhibited thicker PNS and CNS myelin sheaths, and PNS myelin abnormalities, such as tomacula and myelin infoldings/outfoldings, centered around the paranodes and Schmidt Lanterman incisures. These effects were corrected by rapamycin treatmentin vivo Importantly, Akt activity in the transgenic mice did not induce myelination of nonmyelinating Schwann cells in the sympathetic trunk or Remak fibers of the dorsal roots, although, in those structures, they wrapped membranes redundantly around axons. Together, our data indicate that Akt is crucial for PNS myelination driving axonal wrapping by unmyelinated and myelinated Schwann cells and enhancing myelin protein synthesis in myelinating Schwann cells. SIGNIFICANCE STATEMENT: Although the role of the key serine/threonine kinase Akt in promoting CNS myelination has been demonstrated, its role in the PNS has not been established and remains uncertain. This work reveals that Akt controls several key steps of the PNS myelination. First, its activity promotes membrane production and axonal wrapping independent of a transcriptional effect. In myelinated axons, it also enhances myelin thickness through the mTOR pathway. Finally, sustained Akt activation in Schwann cells leads to hypermyelination/dysmyelination, mimicking some features present in neuropathies, such as hereditary neuropathy with liability to pressure palsies or demyelinating forms of Charcot-Marie-Tooth disease. Together, these data demonstrate the role of Akt in regulatory mechanisms underlying axonal wrapping and myelination in the PNS.
PMCID:4837684
PMID: 27098694
ISSN: 1529-2401
CID: 2079372

Inhibition of Gli1 mobilizes endogenous neural stem cells for remyelination

Samanta, Jayshree; Grund, Ethan M; Silva, Hernandez M; Lafaille, Juan J; Fishell, Gord; Salzer, James L
Enhancing repair of myelin is an important but still elusive therapeutic goal in many neurological disorders. In multiple sclerosis, an inflammatory demyelinating disease, endogenous remyelination does occur but is frequently insufficient to restore function. Both parenchymal oligodendrocyte progenitor cells and endogenous adult neural stem cells resident within the subventricular zone are known sources of remyelinating cells. Here we characterize the contribution to remyelination of a subset of adult neural stem cells, identified by their expression of Gli1, a transcriptional effector of the sonic hedgehog pathway. We show that these cells are recruited from the subventricular zone to populate demyelinated lesions in the forebrain but never enter healthy, white matter tracts. Unexpectedly, recruitment of this pool of neural stem cells, and their differentiation into oligodendrocytes, is significantly enhanced by genetic or pharmacological inhibition of Gli1. Importantly, complete inhibition of canonical hedgehog signalling was ineffective, indicating that the role of Gli1 both in augmenting hedgehog signalling and in retarding myelination is specialized. Indeed, inhibition of Gli1 improves the functional outcome in a relapsing/remitting model of experimental autoimmune encephalomyelitis and is neuroprotective. Thus, endogenous neural stem cells can be mobilized for the repair of demyelinated lesions by inhibiting Gli1, identifying a new therapeutic avenue for the treatment of demyelinating disorders.
PMCID:4970518
PMID: 26416758
ISSN: 1476-4687
CID: 1789792

Myelination: Actin Disassembly Leads the Way

Samanta, Jayshree; Salzer, James L
The mechanisms that drive the spiral wrapping of the myelin sheath around axons are poorly understood. Two papers in this issue of Developmental Cell demonstrate that actin disassembly, rather than actin assembly, predominates during oligodendrocyte maturation and is critical for the genesis of the central myelin sheath.
PMCID:4970517
PMID: 26218317
ISSN: 1878-1551
CID: 1698312

Schwann Cell Myelination

Salzer, James L
Myelinated nerve fibers are essential for the rapid propagation of action potentials by saltatory conduction. They form as the result of reciprocal interactions between axons and Schwann cells. Extrinsic signals from the axon, and the extracellular matrix, drive Schwann cells to adopt a myelinating fate, whereas myelination reorganizes the axon for its role in conduction and is essential for its integrity. Here, we review our current understanding of the development, molecular organization, and function of myelinating Schwann cells. Recent findings into the extrinsic signals that drive Schwann cell myelination, their cognate receptors, and the downstream intracellular signaling pathways they activate will be described. Together, these studies provide important new insights into how these pathways converge to activate the transcriptional cascade of myelination and remodel the actin cytoskeleton that is critical for morphogenesis of the myelin sheath.
PMCID:4526746
PMID: 26054742
ISSN: 1943-0264
CID: 1626192