Calcineurin/NFAT signaling is required for neuregulin-regulated Schwann cell differentiation.
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.
Kao
Shih-Chu
SC
Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
Wu
Hai
H
Xie
Jianming
J
Chang
Ching-Pin
CP
Ranish
Jeffrey A
JA
Graef
Isabella A
IA
Crabtree
Gerald R
GR
D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D018920:Coculture Techniques; D051767:Early Growth Response Protein 2 / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology; D051379:Mice; D009186:Myelin Sheath / Q000502:physiology; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009432:Neural Crest / Q000166:cytology / Q000378:metabolism; D020880:Neuregulins / Q000378:metabolism*; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3; D055757:SOXE Transcription Factors / Q000378:metabolism; D012583:Schwann Cells / Q000166:cytology* / Q000378:metabolism*; D015398:Signal Transduction
D019703:Calcineurin; D002118:Calcium; D051767:Early Growth Response Protein 2; D050778:NFATC Transcription Factors; D020880:Neuregulins; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D055757:SOXE Transcription Factors; C497327:Egr2 protein, mouse; C494009:Nfatc3 protein, mouse; C467907:Nfatc4 protein, mouse; C527924:Sox10 protein, mouse; C524056:Erbb2 protein, mouse