Calcineurin/NFAT Signaling Is Required for Neuregulin-Regulated Schwann Cell Differentiation

Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
Science (Impact Factor: 33.61). 02/2009; 323(5914):651-4. DOI: 10.1126/science.1166562
Source: PubMed


Schwann cells develop from multipotent neural crest cells and form myelin sheaths around axons that allow rapid transmission of action potentials. Neuregulin signaling through the ErbB receptor regulates Schwann cell development; however, the downstream pathways are not fully defined. We find that mice lacking calcineurin B1 in the neural crest have defects in Schwann cell differentiation and myelination. Neuregulin addition to Schwann cell precursors initiates an increase in cytoplasmic Ca2+, which activates calcineurin and the downstream transcription factors NFATc3 and c4. Purification of NFAT protein complexes shows that Sox10 is an NFAT nuclear partner and synergizes with NFATc4 to activate Krox20, which regulates genes necessary for myelination. Our studies demonstrate that calcineurin and NFAT are essential for neuregulin and ErbB signaling, neural crest diversification, and differentiation of Schwann cells.

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Available from: Ching-Pin Chang, Oct 17, 2014
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    • "They upregulate cytokines required for T cell proliferation and stimulate cell growth and differentiation during the T cell response (Kiani et al., 2000). Four of the five known NFAT proteins are part of the T cell response mechanism (Macian, 2005), but NFAT proteins also take part in different regulatory mechanisms of other cells (Crabtree and Olson, 2002; Graef et al., 2001; Hogan et al., 2003; Kao et al., 2009). The C-terminal half of the 930-residue NFAT contains two domains involved in binding DNA and AP-1 and has been characterized structurally (Chen et al., 1998; Jin et al., 2003; Wolfe et al., 1997; Zhou et al., 1998). "
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    • "In addition our enrichment analysis reveals a statistically significant association of PPP3CA with cell differentiation signaling. This result is consistent with the report by Kao et al. that the differentiation of Schwann cells requires the activity of the PPP3CA phosphatase (Kao et al., 2009). Similarly, we found that DUSP26 is significantly correlated with the DNA damage response. "
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    • "Because of the early lethality of Smad1 À/À embryos (Lechleider et al., 2001), we generated conditional knockout (cKO) mice (Smad1 fl/À ;Nestin-Cre; hereafter referred to as Smad1 cKO Nes ). Nestin-Cre induces recombination in neural progenitor cells and is expected to ablate Smad1 specifically in DRG sensory neurons as early as E11.5 while sparing Schwann cells (Dubois et al., 2006; Kao et al., 2009; Tronche et al., 1999), which we confirmed using the Rosa26-EYFP STOP reporter line (Figures S1C–S1E). First, western blotting confirmed that Smad1 was markedly reduced in E12.5 mutant DRGs as compared with Smad1 fl/+ ;Nestin-Cre control littermates (Figure 1E). "
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