Axonal neuregulin 1 is a rate limiting but not essential factor for nerve remyelination

Fricker, Florence R.; Antunes-Martins, Ana; Galino, Jorge; Paramsothy, Remi; Russa, Federica La; Perkins, James R.; Goldberg, Rebecca; Brelstaff, Jack; Zhu, Ning; McMahon, Stephen B.; Orengo, Christine; Garratt, Alistair N.; Birchmeier, Carmen; Bennett, David L.H.

doi:10.1093/brain/awt148

Cited by 77 publications

(85 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Neuregulin release is of particular importance for neurite outgrowth as well as for migration and association of Schwann cells with axons and, thereby, myelination of such outgrowing neurites (44)(45)(46). NRG1 type 1 and NRG1 type III catalyze two subsequent steps: neurite outgrowth followed by myelination.…”

Section: Resultsmentioning

confidence: 99%

Distinct Intracellular Domain Substrate Modifications Selectively Regulate Ectodomain Cleavage of NRG1 or CD44

Parra

Hartmann

Schubach

et al. 2015

Molecular and Cellular Biology

View full text Add to dashboard Cite

bEctodomain cleavage by A-disintegrin and -metalloproteases (ADAMs) releases many important biologically active substrates and is therefore tightly controlled. Part of the regulation occurs on the level of the enzymes and affects their cell surface abundance and catalytic activity. ADAM-dependent proteolysis occurs outside the plasma membrane but is mostly controlled by intracellular signals. However, the intracellular domains (ICDs) of ADAM10 and -17 can be removed without consequences for induced cleavage, and so far it is unclear how intracellular signals address cleavage. We therefore explored whether substrates themselves could be chosen for proteolysis via ICD modification. We report here that CD44 (ADAM10 substrate), a receptor tyrosine kinase (RTK) coreceptor required for cellular migration, and pro-NRG1 (ADAM17 substrate), which releases the epidermal growth factor (EGF) ligand neuregulin required for axonal outgrowth and myelination, are indeed posttranslationally modified at their ICDs. Tetradecanoyl phorbol acetate (TPA)-induced CD44 cleavage requires dephosphorylation of ICD serine 291, while induced neuregulin release depends on the phosphorylation of several NRG1-ICD serines, in part mediated by protein kinase C␦ (PKC␦). Downregulation of PKC␦ inhibits neuregulin release and reduces ex vivo neurite outgrowth and myelination of trigeminal ganglion explants. Our results suggest that specific selection among numerous substrates of a given ADAM is determined by ICD modification of the substrate. Many transmembrane proteins on the cell surface are subject to proteolytic cleavage of their ectodomains, predominantly by metalloproteases (ectodomain shedding) (1-3). Ectodomain shedding regulates numerous important molecules involved in signal transfer between the extracellular space and the cell's interior and thus influences many cellular functions (1, 3). This includes, for example, the biological availability of epidermal growth factor (EGF) receptor ligands such as neuregulin (NRG1) (4, 5) and the modulation of complex cellular phenotypes required for contact inhibition of cells involving the hyaluronic acid receptor CD44 (4). NRG1 regulates neurite outgrowth and myelination but also has important functions in the development of other organs, for instance, the heart (6-9). When bound to hyaluronan, CD44 triggers a proliferation-inhibitory pathway (10-12). On the other hand, cancer stem cells carry CD44 (13-15), and, in this context, CD44 promotes tumor growth and metastasis (16-21), likely via alternative splice forms of CD44 that act as growth factor-enriching coreceptors for receptor tyrosine kinases (RTKs) (22,23).Inappropriate proteolysis of a number of shed substrates is associated with diseases when cleavage is either upregulated or reduced (24, 25). Equally, total knockout of substrates leads to significant phenotypes (26,27). This indicates that ectodomain cleavage requires tight regulation. How ectodomain cleavage is regulated and made substrate specific is largely unknown to date.The metallop...

show abstract

Section: Resultsmentioning

confidence: 99%

Distinct Intracellular Domain Substrate Modifications Selectively Regulate Ectodomain Cleavage of NRG1 or CD44

Parra

Hartmann

Schubach

et al. 2015

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…A number of seminal studies showed that early upregulation of the MAP kinases (MAPKs), c-Jun (37), ERK (35), and p38 (36) in Schwann cells after injury drove dedifferentiation and proliferation of these glial cells and that prolonging or eliminating their presence markedly altered myelin clearance, regeneration, and remyelination. In addition, suppression or loss of NRGs or ErbBs, which drives multiple aspects of Schwann cell and axon biology after injury, such as de-and remyelination (31,43), Schwann cell de-and redifferentiation (31,32), regeneration (30), and neuromuscular junction reinnervation (30), disrupts regeneration and remyelination (31).…”

Section: Discussionmentioning

confidence: 99%

AlphaB-crystallin regulates remyelination after peripheral nerve injury

Lim

Nakanishi

Hoghooghi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

AlphaB-crystallin (αBC) is a small heat shock protein that is constitutively expressed by peripheral nervous system (PNS) axons and Schwann cells. To determine what role this crystallin plays after peripheral nerve damage, we found that loss of αBC impaired remyelination, which correlated with a reduced presence of myelinating Schwann cells and increased numbers of nonmyelinating Schwann cells. The heat shock protein also seems to regulate the cross-talk between Schwann cells and axons, because expected changes in neuregulin levels and ErbB2 receptor expression after PNS injury were disrupted in the absence of αBC. Such dysregulations led to defects in conduction velocity and motor and sensory functions that could be rescued with therapeutic application of the heat shock protein in vivo. Altogether, these findings show that αBC plays an important role in regulating Wallerian degeneration and remyelination after PNS injury.T he robust regenerative capacity of the damaged peripheral nervous system (PNS) is partly determined by cellular and molecular events that occur in the nerve segment distal to the injury site (1). For instance, during Wallerian degeneration, influx of calcium into the damaged nerve within 12-24 h of PNS injury activates proteases (2) that result in cytoskeletal breakdown and subsequent disintegration of the axon membrane. This axon degeneration is then followed by breakdown of the myelin sheath within 2 d (3). Schwann cells, the glial cells that characterize the PNS, subsequently undergo a number of reactive physiological changes that benefit the damaged axon. Within 48 h of peripheral nerve damage, myelinating Schwann cells decrease their expression of myelin proteins, such as myelin basic protein (MBP), peripheral myelin protein 22, and protein 0 (P0) (4), and along with their nonmyelinating counterparts, revert to a nonmyelinating phenotype (4). At ∼3-4 d postinjury, the dedifferentiated Schwann cells proliferate (5-7) and align within the basal lamina to form bands of Büngner that provide a structural and trophic supportive substrate for regenerating axons. These Schwann cells secrete neurotrophic factors that provide trophic sustenance to damaged neurons until they reestablish contact with their targets (8) and produce extracellular matrix molecules that encourage and guide outgrowing axons (9), whereas secretion of chemokines is thought to mediate the infiltration of blood-derived macrophages, which along with Schwann cells, phagocytose myelin debris and its associated axon growth inhibitors (9). Finally, based on the level of neuregulin 1 Types I and III on Schwann cells and axons, respectively, and their binding to their cognate receptors ErbB2/ ErbB3 on Schwann cells, these glia will revert to a myelinating or ensheathing phenotype on contact with regrowing axons (10). Altogether, these morphological and physiological changes in Schwann cells create an environment that encourages longdistance axon growth.In humans, however, regrowth of damaged peripheral nerves is often incomplete, wh...

show abstract

“…Studies of mouse mutants with genetic inactivation in neuregulin 1 signaling to test whether neuregulin 1 drives the proliferation of developing Schwann cells are not available (for discussion, see Jessen and Mirsky 2012). In adult mice, injury-induced Schwann cell proliferation appears to be neuregulin 1 independent (Atanasoski et al 2006;Fricker et al 2013).…”

Section: What Drives Schwann Cell Proliferation?mentioning

confidence: 99%

Schwann Cells: Development and Role in Nerve Repair

Jessen

Mirsky

Lloyd

2015

Cold Spring Harb Perspect Biol

550

512

View full text Add to dashboard Cite

Schwann cells develop from the neural crest in a well-defined sequence of events. This involves the formation of the Schwann cell precursor and immature Schwann cells, followed by the generation of the myelin and nonmyelin (Remak) cells of mature nerves. This review describes the signals that control the embryonic phase of this process and the organogenesis of peripheral nerves. We also discuss the phenotypic plasticity retained by mature Schwann cells, and explain why this unusual feature is central to the striking regenerative potential of the peripheral nervous system (PNS).T he myelin and nonmyelin (Remak) Schwann cells of adult nerves originate from the neural crest in well-defined developmental steps ( Fig. 1). This review focuses on embryonic development (for additional information on myelination, see Salzer 2015). We also discuss how the ability to change between differentiation states, a characteristic attribute of developing cells, is retained by mature Schwann cells, and explain how the ability of Schwann cells to change phenotype in response to injury allows the peripheral nervous system (PNS) to regenerate after damage. TWO TYPES OF EMBRYONIC NERVESAdult nerves are stable structures in which the nerve fibers are protected structurally by a collagen-rich, vascularized extracellular matrix (the endoneurium) linked to the basal lamina surrounding each axon -Schwann cell unit. The endoneurial environment is further protected by a surrounding multilayered cellular tube (the perineurium) that shields the nerve fibers from unwanted cells and molecules (Fig. 2).A more dynamic and radically different structure, reminiscent of axon -glial organization in the central nervous system (CNS), is seen in early embryonic nerves (embryo day E14/15 in rat hind limb and E12/13 in mouse). These nerves consist of tightly packed axons and flattened, glial cell processes without significant extracellular space, matrix, or basal lamina. The glial cell bodies lie among the axons inside the nerve or at the nerve surface. These cells represent the first stage of the Schwann cell lineage, Schwann cell precursors (Figs. 3 and 4).

show abstract

Axonal neuregulin 1 is a rate limiting but not essential factor for nerve remyelination

Cited by 77 publications

References 66 publications

Distinct Intracellular Domain Substrate Modifications Selectively Regulate Ectodomain Cleavage of NRG1 or CD44

Distinct Intracellular Domain Substrate Modifications Selectively Regulate Ectodomain Cleavage of NRG1 or CD44

AlphaB-crystallin regulates remyelination after peripheral nerve injury

Schwann Cells: Development and Role in Nerve Repair

Contact Info

Product

Resources

About