Sox10 regulates ciliary neurotrophic factor gene expression in Schwann cells

doi:10.1073/pnas.0602332103

Sox10 regulates ciliary neurotrophic factor gene expression in Schwann cells

*Institute for Clinical Neurobiology, University of Wuerzburg, D-97080 Wuerzburg, Germany;
^†Department of Molecular Neuropathology, Tokyo Metropolitan Institute for Neuroscience, 2-6 Musashidai, Fuchu-shi, Tokyo 183-8526, Japan; and
^‡Institute of Biochemistry, Erlangen University, D-91054 Erlangen, Germany

Communicated by Hans Thoenen, Max Planck Institute of Neurobiology, Martinsried, Germany, March 29, 2006 (received for review November 16, 2005)

Abstract

Ciliary neurotrophic factor (Cntf) plays an essential role in postnatal maintenance of spinal motoneurons. Whereas the expression of this neurotrophic factor is low during embryonic development, it is highly up-regulated after birth in myelinating Schwann cells of rodents. To characterize the underlying transcriptional mechanisms, we have analyzed and compared the effects of various glial transcription factors. In contrast to Pit-1, Oct-1, Unc-86 homology region (POU) domain class 3, transcription factor 1 (Oct6/SCIP/Tst-1) and paired box gene 3 (Pax3), SRY-box-containing gene 10 (Sox10) induces Cntf expression in Schwann cells. Subsequent promoter analysis using luciferase reporter gene and EMSA identified the corresponding response elements within the Cntf promoter. Overexpression of Sox10 in primary sciatic nerve Schwann cells leads to a >100-fold up-regulation of Cntf protein, and suppression of Sox10 by RNA interference in the spontaneously immortalized Schwann cell line 32 reduces Cntf expression by >80%. Mice with heterozygous inactivation of the Sox10 gene show significantly reduced Cntf protein levels in sciatic nerves, indicating that Sox10 is necessary and sufficient for regulating Cntf expression in the peripheral nervous system.

Footnotes

^§To whom correspondence should be addressed at:
Institute for Clinical Neurobiology, Josef-Schneider-Strasse 11, University of Wuerzburg, D-97080 Wuerzburg, Germany.
E-mail: sendtner{at}mail.uni-wuerzburg.de
Author contributions: Y.I., S.W., and M.S. designed research; N.F., A.C., W.R., H.B., K.W., and M.W. contributed new reagents/analytic tools; and Y.I., S.W., and M.S. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations:

Abbreviations:

Cntf,

ciliary neurotrophic factor;

IMS32,

immortalized Schwann cell line 32;

S1, S2 and S3,

Sox10 high mobility group type DNA-binding motifs 1, 2 and 3;

S1m, S2m and S3m,

mutated S1, S2 and S3;

Pn,

postnatal day n.