Schwann Cell Dedifferentiation Is Independent of Mitogenic Signaling and Uncoupled to Proliferation

Abstract

Myelinating Schwann cells (SCs) are highly plastic cells that are able to dedifferentiate and re-enter the cell cycle. However, the molecular signals controlling dedifferentiation are not completely understood. Because a connection between mitogenic signaling and myelin loss has been suggested, we investigated the role of cAMP, a strong inducer of the myelinating phenotype, and mitogenic factors activating receptor tyrosine kinases (RTKs) on SC dedifferentiation. We herein provide evidence indicating that cAMP was required to not only initiate but also maintain a state of differentiation because SCs rapidly dedifferentiated and became competent to resume proliferation upon the removal of cAMP stimulation. Surprisingly, isolated SCs could undergo multiple cycles of differentiation and dedifferentiation upon cAMP addition and removal, respectively, in the absence of mitogenic factors and without entering the cell cycle. Conversely, the activation of RTKs and the ERK cascade by a variety of growth factors, including neuregulin, was not sufficient to initiate dedifferentiation in the presence of cAMP. Importantly, a reduction of cAMP triggered dedifferentiation through a mechanism that required JNK, rather than ERK, activity and an induction of the expression of c-Jun, a transcriptional inhibitor of myelination. In summary, the reversible transition from an undifferentiated to a myelinating state was dependent on cAMP but independent of RTK signaling and cell cycle progression, further indicating that dedifferentiation and proliferation are uncoupled and differentially regulated events in SCs.

The Atypical Guanine-Nucleotide Exchange Factor, Dock7, Negatively Regulates Schwann Cell Differentiation and Myelination

“…Treatment of Schwann cells with structurally different JNK inhibitors, such as JNK inhibitor I or SP600125, promoted dibutyryl cAMP-induced morphological differentiation (Fig. 3G,H ), which is consistent with the finding that JNK signaling is negatively involved in Schwann cell differentiation and myelination (Kaempchen et al, 2003;Parkinson et al, 2004;Monje et al, 2010).…”

“…Schwann cells were plated for experiments on collagen (type I)-coated culture dishes or wells. For morphological differentiation experiments, rat Schwann cells were cultured, first in Sato medium (Bottenstein and Sato, 1979) for 1 d, and then in Sato medium containing 0, 0.3, or 1 mM dibutyryl cAMP for an additional 2 d (Sobue et al, 1986;D'Antonio et al, 2006;Monje et al, 2010). For a proliferation assay, Schwann cells were seeded at 1 ϫ 10 5 cells/3.5 cm dish, cultured in the presence of 10 ng/ml neuregulin-1 (R&D Systems) and 5 M forskolin for 0 -48 h, and counted using a hemocytometer.…”

“…processes, accompanied by the expression of myelin marker proteins such as MBP and MPZ (Sobue et al, 1986;D'Antonio et al, 2006;Monje et al, 2010). Differentiated Schwann cells often form a myelin web-like structure with fenestrated cytoplasmic sheets (Sobue et al, 1986;D'Antonio et al, 2006;Monje et al, 2010; see Fig.…”

“…Differentiated Schwann cells often form a myelin web-like structure with fenestrated cytoplasmic sheets (Sobue et al, 1986;D'Antonio et al, 2006;Monje et al, 2010; see Fig. 2B, bottom panels).…”

Stem Like Cells and Androgen Deprivation in Prostate Cancer

“…Moreover, enriched SLC populations have been reported in several tumor-free tissues following local damage (Beltrami et al, 2003;Amcheslavsky et al, 2009 (Zipori, 2009). Several recent studies have also documented de-differentiation in mature cells (Brawley & Matunis, 2004;Monje et al, 2010;Red-Horse et al, 2010;Shoshani & Zipori, 2011) During tumor recurrence/progression, the de-differentiated SLC can re-differentiate back into the original tumor, or under other conditions, they could trans-differentiate to a different phenotype. Our TRAMP mice castrated at 12 weeks of age all eventually developed prostate cancer, including distant metastasis in over 70% of the animals (Y.…”