Evidence that sensory axons are mitogenic for Schwann cells

Wood, Patrick M.; Bunge, Richard P.

doi:10.1038/256662a0

Cited by 400 publications

(198 citation statements)

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“…Signaling through MEK-ERK and PI3K-Akt-cAMP is one key modulator of SC proliferation, and it has been hypothesized that a component of the mitogenic activity of axons (37) involves the induction of cAMP in SCs (38). However, the only known axonal mitogen for SCs belongs to the neuregulin family, and our results show that neuregulin stimulation does not directly trigger PKA activity in human SCs (Fig.…”

Section: Adenosine and Epinephrine Synergistically Enhance Sc Prolifementioning

confidence: 47%

Protein Kinase A-mediated Gating of Neuregulin-dependent ErbB2-ErbB3 Activation Underlies the Synergistic Action of cAMP on Schwann Cell Proliferation

Monje

Athauda

Wood

2008

Journal of Biological Chemistry

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In Schwann cells (SCs), cyclic adenosine monophosphate (cAMP) enhances the action of neuregulin, the most potent known mitogen for SCs, by synergistically increasing the activation of two crucial signaling pathways: ERK and Akt. However, the underlying mechanism of cross-talk between neuregulin and cAMP signaling remains mostly undefined. Here, we report that the activation of protein kinase A (PKA), but not that of exchange protein activated by cAMP (EPAC), enhances S-phase entry of SCs by synergistically enhancing the ligand-dependent tyrosine phosphorylation/activation of the neuregulin co-receptor, ErbB2-ErbB3. The role of PKA in neuregulin-ErbB signaling was confirmed using PKA inhibitors, pathway-selective cAMP analogs, and natural ligands stimulating PKA activity in SCs, such as adenosine and epinephrine. Two basic observations defined the synergistic action of PKA as "gating" for neuregulinErbB signaling: 1) the activation of PKA was not sufficient to induce S-phase entry or the activation of either ErbB2 or ErbB3; and 2) the presence of neuregulin was strictly required to ignite ErbB activation and thereby ERK and Akt signaling. However, PKA directly phosphorylated ErbB2 on Thr-686, a highly conserved intracellular regulatory site that was required for the PKA-mediated synergistic enhancement of neuregulin-induced ErbB2-ErbB3 activation and proliferation in SCs. The gating action of PKA on neuregulin-induced ErbB2-ErbB3 activation has important biological significance, because it insures signal amplification into the ERK and Akt pathways without compromising either the neuregulin dependence or the high specificity of ErbB signaling pathways.

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Section: Adenosine and Epinephrine Synergistically Enhance Sc Prolifementioning

confidence: 47%

Protein Kinase A-mediated Gating of Neuregulin-dependent ErbB2-ErbB3 Activation Underlies the Synergistic Action of cAMP on Schwann Cell Proliferation

Monje

Athauda

Wood

2008

Journal of Biological Chemistry

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“…When mitoses cease, SC quickly recover their SC phenotype with rhythmic undulations while migration speed increased to 92±20 µ/h. Thus, in spite of dramatic modification of shape, structure and behavior during mitotic stimulation, SC subsequently recover their unique motility pattern which might be essential for their myelinating function.Rat Schwann cells (SC), the myelin-form-ing cells of the peripheral nervous system, can now be cultured in isolation by using two different techniques [1][2][3]. In the first, rat dorsal root ganglia obtained just before birth are explanted and treated with antimitotic agents for a few days.…”

mentioning

confidence: 99%

“…Rat Schwann cells (SC), the myelin-form-ing cells of the peripheral nervous system, can now be cultured in isolation by using two different techniques [1][2][3]. In the first, rat dorsal root ganglia obtained just before birth are explanted and treated with antimitotic agents for a few days.…”

mentioning

confidence: 99%

“…In the first, rat dorsal root ganglia obtained just before birth are explanted and treated with antimitotic agents for a few days. After 10 days, the ganglia are excised and a "Schwann cell bed" is developed after the neurites are eliminated [1,2]. In the second technique, dissociation of newborn rat sciatic nerve results in a mixed population of SC and fibroblasts, which after 2 days of culturing are identified by their respective surface antigenic markers Ran 1 and Thy 1.1 [3,4].…”

mentioning

confidence: 99%

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Structure and behavior of rat primary and secondary Schwann cells in vitro

Dubois‐Dalcq

Rentier

et al. 1981

Experimental Cell Research

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SUMMARYThe structure and motility of isolated rat primary (I) Schwann cells (SC) have been compared to that of subcultured (II) SC during and after mitotic stimulation. I SC contain myelin components which persist for 2 weeks in serum-free medium while they rapidly disappear in medium containing serum and high glucose concentration. These components were never detected in II SC. Both I SC and II SC after their mitotic phase are spindle-shaped, contain many intermediate and actin filaments, have no basement membrane but show intense migratory and undulatory activities. Rare fibroblasts in I cultures are recognized by their extremely variable shape, the presence of Thy 1.1 antigen in their membrane and their intense edge ruffling alternating with abrupt translocation. In contrast, I SC movements consist of intracellular translocation of nuclei along SC processes, which retract and extend constantly, and in slow rhythmic undulation episodes (2.3±0.2/min) alternating with migration at 135±50 µ/h. The total number of these episodes per day in serum-free medium is rigorously identical for different cells (166.3±0.2) and this uniformity of frequency suggests a genotypic basis. Cycles, consisting of an undulation episode followed by a resting interval, have mean durations of 8.6±4.1 min and a sharp peak of occurrence at 6 min, with exponential distribution of the longer periods. Motility of II SC is considerably inhibited during mitotic stimulation by cholera toxin and a pituitary extract while SC phenotype has changed to a flat multipolar cell with prominent Golgi and ribosomes. Migration is reduced to 24±2 µ/h and only 2 % of the SC show pulsations of the same periodicity as the I SC undulations. A dramatic increase in pulsation frequency occurs 6-12 h after removal of mitogenic factors when 80% of II SC start pulsating twice as fast for 2-3 days. When mitoses cease, SC quickly recover their SC phenotype with rhythmic undulations while migration speed increased to 92±20 µ/h. Thus, in spite of dramatic modification of shape, structure and behavior during mitotic stimulation, SC subsequently recover their unique motility pattern which might be essential for their myelinating function.Rat Schwann cells (SC), the myelin-form-ing cells of the peripheral nervous system, can now be cultured in isolation by using two different techniques [1][2][3]. In the first, rat dorsal root ganglia obtained just before birth are explanted and treated with antimitotic agents for a few days. After 10 days, the ganglia are excised and a "Schwann cell bed" is developed after the neurites are eliminated [1,2]. In the second technique, dissociation of newborn rat sciatic nerve results in a mixed population of SC and fibroblasts, which after 2 days of culturing are identified by their respective surface antigenic markers Ran 1 and Thy 1.1 [3,4]. In these cultures, fibroblast growth is first inhibited by AraC treatment and subsequently, by complement-mediated killing of Thy 1.1 positive cells [3]. SC growth can then be intensely stimulated by pi...

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“…The further development of oligo-dendrocytes may well depend on signals from other cell-types Bologa et al, 1982;Mithen et al, 1983). It seems likely that central myelination requires signals derived from neuronal perikarya and/or their axons, similar to what has been shown for Schwann cells in the periferal nervous system (Wood and Bunge, 1975).…”

Section: Discussionmentioning

confidence: 67%

Culture of rat cerebral oligodendrocytes in a serum-free, chemically defined medium

Koper

Lopes‐Cardozo

Romijn

et al. 1984

Journal of Neuroscience Methods

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Kew'ords: oligodendrocyte--primary culture--serum-free medium--chemically defined medium--brain cells--rat brain Oligodendrocytes were isolated from the cerebra of young rats (5-10 days old) by trypsinization of the tissue followed by cell separation on Percoll gradients. The isolation was carried out in physiological, isotonic media. The cell yield was 2-4 × 106 cells per brain; the plating efficiency was >/70%. Isolated cells were seeded on poly-L-lysine-coated culture dishes and maintained in a serum-free, chemically defined medium for at least 30 days. After 10 days in culture 67+10% of the surviving cells were oligodendrocytes, as judged by immunocytochemical and morphological criteria, whereas most of the other cells reacted positively with antiserum against glial fibrillary acidic protein. The expression of typical oligodendrocyte markers (2':3'-cyclic-nucleotide 3'-phosphodiesterase, galactocerebrosides and myelin basic protein) was greatly enhanced under these serum-free conditions as compared with cultures in serum-containing medium. The antigenic markers (galactocerebrosides, myelin basic protein) were absent in the freshly isolated cells but could be detected after 3 days in culture by immunocytochemistry. The activity of 2':3'-cyclic-nucleotide 3'-phosphodiesterase increased from 75 nmol min 1 mg 1 protein on day 4 to 400 nmol min-1 mg 1 protein on day 14 in culture.

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Evidence that sensory axons are mitogenic for Schwann cells

Cited by 400 publications

References 4 publications

Protein Kinase A-mediated Gating of Neuregulin-dependent ErbB2-ErbB3 Activation Underlies the Synergistic Action of cAMP on Schwann Cell Proliferation

Protein Kinase A-mediated Gating of Neuregulin-dependent ErbB2-ErbB3 Activation Underlies the Synergistic Action of cAMP on Schwann Cell Proliferation

Structure and behavior of rat primary and secondary Schwann cells in vitro

Culture of rat cerebral oligodendrocytes in a serum-free, chemically defined medium

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