scholarly journals GPR56/ADGRG1 regulates development and maintenance of peripheral myelin

2018 ◽  
Vol 215 (3) ◽  
pp. 941-961 ◽  
Author(s):  
Sarah D. Ackerman ◽  
Rong Luo ◽  
Yannick Poitelon ◽  
Amit Mogha ◽  
Breanne L. Harty ◽  
...  
Keyword(s):  
Nervous System ◽  
Peripheral Nervous System ◽  
Schwann Cells ◽  
Myelin Sheath ◽  
Underlying Mechanism ◽  
Scaffolding Protein ◽  
Rodent Models ◽  
Myelin Thickness ◽  
Radial Sorting ◽  
Rhoa Signaling

Myelin is a multilamellar sheath generated by specialized glia called Schwann cells (SCs) in the peripheral nervous system (PNS), which serves to protect and insulate axons for rapid neuronal signaling. In zebrafish and rodent models, we identify GPR56/ADGRG1 as a conserved regulator of PNS development and health. We demonstrate that, during SC development, GPR56-dependent RhoA signaling promotes timely radial sorting of axons. In the mature PNS, GPR56 is localized to distinct SC cytoplasmic domains, is required to establish proper myelin thickness, and facilitates organization of the myelin sheath. Furthermore, we define plectin—a scaffolding protein previously linked to SC domain organization, myelin maintenance, and a series of disorders termed “plectinopathies”—as a novel interacting partner of GPR56. Finally, we show that Gpr56 mutants develop progressive neuropathy-like symptoms, suggesting an underlying mechanism for peripheral defects in some human patients with GPR56 mutations. In sum, we define Gpr56 as a new regulator in the development and maintenance of peripheral myelin.

scholarly journals Essential and distinct roles for cdc42 and rac1 in the regulation of Schwann cell biology during peripheral nervous system development

2007 ◽  
Vol 177 (6) ◽  
pp. 1051-1061 ◽  
Author(s):  
Yves Benninger ◽  
Tina Thurnherr ◽  
Jorge A. Pereira ◽  
Sven Krause ◽  
Xunwei Wu ◽  
...  
Keyword(s):  
Nervous System ◽  
Schwann Cell ◽  
Peripheral Nervous System ◽  
Schwann Cells ◽  
Rho Gtpases ◽  
Cell Biology ◽  
System Development ◽  
Nervous System Development ◽  
Conditional Gene Targeting ◽  
Radial Sorting

During peripheral nervous system (PNS) myelination, Schwann cells must interpret extracellular cues to sense their environment and regulate their intrinsic developmental program accordingly. The pathways and mechanisms involved in this process are only partially understood. We use tissue-specific conditional gene targeting to show that members of the Rho GTPases, cdc42 and rac1, have different and essential roles in axon sorting by Schwann cells. Our results indicate that although cdc42 is required for normal Schwann cell proliferation, rac1 regulates Schwann cell process extension and stabilization, allowing efficient radial sorting of axon bundles.

scholarly journals Dependence on Schwann Cell-Derived Laminin-γ1 Differentiates Early Lymphoid and Myeloid Development

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 37-37
Author(s):  
Kristin Komnick ◽  
Jennifer May ◽  
Pouneh Kermani ◽  
Sreemanti Basu ◽  
Irene Hernandez ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Nervous System ◽  
Schwann Cell ◽  
Peripheral Nerve ◽  
Peripheral Nervous System ◽  
Schwann Cells ◽  
Adrenergic Nerve ◽  
Spleen Size ◽  
Mouse Line ◽  
Myeloid Development

Blood cell production is regulated by peripheral nerve fibers that innervate the bone marrow. However, little is known about the development or maintenance of hematopoietic innervation. Schwann cells (SCs) are the primary axon 'support cells' of the peripheral nervous system (PNS), and abnormal SC development is sufficient to impair peripheral nerve function. SCs are also the primary repair cell for the PNS which makes them an attractive therapeutic target for normalization of drug or malignancy-induced 'hematopoietic neuropathy'. We hypothesized that neural regulation of hematopoiesis is dependent on SC development. To test this hypothesis, we used the Myelin Protein Zero-Cre (MP0-Cre); Lamc1fl/fl mouse line in which laminin-γ1 expression is deleted from SC precursors and their progeny1. Early SC maturation is dependent on autocrine SC precursor-derived molecules such as laminin-γ1. SC differentiation arrests prior to axon sorting and ensheathment in MP0-Cre; Lamc1fl/fl mice, and causes a global peripheral neuropathy that persists throughout the lifetime of the animal. Preliminary hematopoietic analysis of 'steady state' MP0-Cre; Lamc1fl/fl and littermate control mice has shown the following: (1) MP0-Cre; Lamc1fl/fl bone marrow is innervated, and Cre-mediated gene recombination occurs in cells immunophenotypically consistent with SCs throughout the peripheral nervous system, including those in the bone marrow; (2) MP0-Cre; Lamc1fl/fl mice are lymphopenic but not neutropenic; (3) MP0-Cre; Lamc1fl/fl mice have significantly reduced spleen size and cellularity; and (4) MP0-Cre; Lamc1fl/fl bone marrow has an ~50% reduction in Lin-Sca-1+Kit+(LSK) cells (measured as a percentage of the Lin- compartment of the bone marrow). These results are consistent with earlier work by our groups in which we found that global Lamc1 gene deletion in adult mice induced peripheral blood lymphopenia, reduced spleen size, and a niche-dependent reduction of lymphoid progenitor and precursor cells that was secondary to increased lymphoid precursor cell apoptosis and reduced proliferation (UBC-CreERT2; Lamc1fl/fl mouse line). As with the SC-specific laminin-γ1 deficient mice, myelopoiesis was preserved in the UBC-CreERT2; Lamc1fl/fl mice. Based on results from MP0-Cre; Lamc1fl/fl and UBC-CreERT2; Lamc1fl/fl mice, we conclude that early lymphoid but not myeloid development requires laminin-γ1 expression by MP0-Cre-targetted niche cells, i.e. Schwann Cells. Our results are consistent with reports from other labs that hematopoietic sympathetic neuropathy promotes aberrant myeloid expansion at the expense of lymphopoiesis2. Going forward, we will determine whether lymphopoietic development is dependent on global versus laminin-specific SC-derived cues, and whether these signals are transmitted directly between SCs and lymphoid biased HSPCs or indirectly via other components of the hematopoietic niche. We anticipate that this line of investigation will provide molecular insights and pharmacologic targets for prevention and or normalization of the 'hematopoietic neuropathy' induced by diabetes, aging, neurotoxic chemotherapies and myeloid malignancies. REFERENCES: 1 Yu, W. M., Feltri, M. L., Wrabetz, L., Strickland, S. & Chen, Z. L. Schwann cell-specific ablation of laminin gamma1 causes apoptosis and prevents proliferation. J Neurosci25, 4463-4472, doi:10.1523/JNEUROSCI.5032-04.2005 (2005). 2 Maryanovich, M. et al. Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche. Nat Med24, 782-791, doi:10.1038/s41591-018-0030-x (2018). Disclosures No relevant conflicts of interest to declare.

Neurofilaments and pathologies of the Peripheral Nervous System

2014 ◽  
Author(s):  
◽  
Jeffrey Dale
Keyword(s):  
Nervous System ◽  
Peripheral Nervous System ◽  
Conduction Velocity ◽  
Radial Growth ◽  
Stride Length ◽  
Wild Type ◽  
Axon Diameter ◽  
Internodal Length ◽  
Axonal Diameter ◽  
Myelin Thickness

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] The efficiency of signal propagation in the peripheral nervous system (PNS) is maximized by myelination and axon diameter. Myelination induces axonal expansion through radial growth. Radial growth is dependent on neurofilaments (NFs) that can be made up of the neurofilament light (NF-L) subunit in association with either the neurofilament medium (NF-M) or neurofilament heavy (NF-H) subunit. Myelin thickness and length (internodal) are established proportional to axon diameter for optimal conduction velocity. Myelin thickness is regulated by total neuregulin I type III (Nrg1 type III) levels present on the axon whereas the mechanisms that control the establishment of internodal length are less understood. My work expands on previous data demonstrating that myelin thickness does not respond to alterations in axonal diameter. In contrast to the previous study, my work describes myelin thickness in the context of decreased axonal diameters. NF subunit mutants that result in varying degrees of altered axonal diameter were used as a tool to study the response of myelin thickness to larger reductions in axonal diameter. At two and six months, g-ratios corresponded to the degree of axonal diameter change. At two months, the size of axons arranged into the following order: wild type > NF-H[superscript [[delta]]Tail] > NF-M[superscript [[delta]]Tail]>NF-(M/H) [superscript [[delta]]Tail]. Correspondingly, g-ratios arranged into the same order indicating the larger the decrease in axon diameter, the greater the proportional increase in myelin thickness. At six months, axon diameters grouped into "wild type" sizes and "NFM?Tail" sizes. Similarly, g-ratios grouped into "wild type" ratios and "NF-M?Tail" ratios indicating that myelin thickness did not respond to increased radial growth. At six months NF-M?Tail mice demonstrated decreased internodal length suggesting that internodal length responded to alterations in axon diameter. My work provides the first evidence of the consequence of altered myelin thickness in isolation. Mice with hypomyelination, alone, demonstrated reduced swing speed and stride length in all limbs. Mutations in proteins specific to myelin result CMT1 that display uniform slowing of conduction velocity. In contrast, CMT2E arises from mutations to axonal proteins resulting in non-uniform slowing of conduction velocity. We generated a mouse model of CMT2E by expressing a hNF-L[superscript E397K] transgene. hNF-L[superscript E397K] expression causes inherent defects to the neurofilament network. As a result, our CMT2E model demonstrates altered myelin thickness in motor and sensory nerves and unilateral gait alterations that include decreased stride length, increased foot drags, and altered coordination of coupled limbs. The correlation between defects observed in our hypomyelination model and our CMT2E model suggest that altered myelin thickness may play a role in CMT2E phenotype. NF accumulations first appear at the NMJs of the diaphragm in SMA?7 mice. Motor axon loss and decreased axonal diameter is observed in the cervical spinal cord which is responsible for innervating the diaphragm. Taken together, these data suggest that inherent NF defects may be present in SMA?7 mice. My work provides a comprehensive analysis of the NF network in a cell, sciatic nerve, where analyses wouldn't be confounded by axonal loss. My analyses demonstrated that total NF levels, trafficking, and deposition were unaffected in SMA?7 mice suggesting that the NF network was uncompromised. Therefore, NF accumulations at the NMJ are most likely due to local alterations to NF dynamics. Furthermore, my work demonstrates that alterations to the transport of retrograde motors and anterograde transport of vital synaptic vesicle proteins coincide with the appearance of NF accumulations.

scholarly journals 3D in vitro peripheral nervous system organoid using mouse primary dorsal root ganglion neurons and Schwann cells

IBRO Reports ◽  
2019 ◽  
Vol 6 ◽  
pp. S124
Author(s):  
Woon-Hae Kim ◽  
Hyun-Gyu Kang ◽  
Taehoon H. Kim ◽  
Yoon Jeong Mo ◽  
Yu Seon Kim ◽  
...  
Keyword(s):  
Nervous System ◽  
Dorsal Root Ganglion ◽  
Peripheral Nervous System ◽  
Schwann Cells ◽  
Dorsal Root ◽  
Dorsal Root Ganglion Neurons ◽  
Ganglion Neurons

Tenascin-R is expressed by Schwann cells in the peripheral nervous system

2001 ◽  
Vol 64 (1) ◽  
pp. 70-78 ◽  
Author(s):  
Rainer Probstmeier ◽  
J�rg Nellen ◽  
Sergio Gloor ◽  
Anton Wernig ◽  
Penka Pesheva
Keyword(s):  
Nervous System ◽  
Peripheral Nervous System ◽  
Schwann Cells

scholarly journals Myelination: all about Rac ‘n’ roll

2007 ◽  
Vol 177 (6) ◽  
pp. 953-955 ◽  
Author(s):  
Jonah R. Chan
Keyword(s):  
Nervous System ◽  
Schwann Cells ◽  
Molecular Mechanisms ◽  
Nerve Bundle ◽  
Effector Molecule ◽  
Downstream Effector ◽  
Rho Family ◽  
Radial Sorting ◽  
Shed Light ◽  
Lamellipodia Formation

During the development of the peripheral nervous system, Schwann cells select individual axons from a nerve bundle and establish a one-to-one relationship through a process termed “radial sorting”. Recent findings identify the Rho family GTPase Rac1 as the downstream effector molecule responsible for process extension and lamellipodia formation in Schwann cells, allowing for proper radial sorting and myelination. These findings begin to shed light on our understanding of the distinct and yet essential molecular mechanisms involved in developmental processes preceding myelination.

scholarly journals Dynamic properties of a reconstituted myelin sheath

2010 ◽  
Vol 24 (6) ◽  
pp. 585-592 ◽  
Author(s):  
W. Knoll ◽  
F. Natali ◽  
J. Peters ◽  
R. Nanekar ◽  
C. Wang ◽  
...  
Keyword(s):  
Nervous System ◽  
Neutron Scattering ◽  
Peripheral Nervous System ◽  
Myelin Sheath ◽  
Lipid Membrane ◽  
Dynamic Properties ◽  
Signal Transmission ◽  
Demyelinating Diseases ◽  
Specific Proteins ◽  
Molecular Components

Myelin is a multilamellar membrane which, wrapping the nerve axons, increases the efficiency of nervous signal transmission. Indeed, the molecular components of the myelin sheath interact tightly with each other and molecules on the axonal surface to drive myelination, to keep both myelin and the axon intact, and to transduce signals from myelin to the axon and vice versa. Myelin is strongly affected in human demyelinating diseases in both the central and peripheral nervous system (CNS and PNS, respectively). Despite the presence of a well-defined set of myelin-specific proteins, little is known about the structure and the dynamics of these proteins, their interactions with the membrane and their influence on myelin stability. We present here the first neutron scattering results on the dynamics of the myelin sheath in PNS and of the interaction between its constituents. Specifically, the human P2 protein is shown to stabilize the lipid membrane upon binding to it.

Sign in / Sign up

Export Citation Format

Share Document