Gating of CNTF Signals by FGF2

Science's STKE  09 Mar 2004:
Vol. 2004, Issue 223, pp. tw90-TW90
DOI: 10.1126/stke.2232004TW90

Ciliary neurotrophic factor (CNTF) promotes differentiation of cortical progenitor cells in rat brain into astrocytes. However, such progenitor cells become responsive to CNTF only later in development. Younger or "early" progenitors are not responsive to CNTF even though they express CNTF receptors and the STAT transcription factors normally activated by CNTF. Song and Ghosh explored the mechanism by which progenitor cells gained competence to respond to CNTF. Thus, they uncovered a new mechanism for permissive regulation of gene expression by fibroblast growth factor 2 (FGF2, another factor that provides developmental cues to the progenitor cells). FGF2 had little or no effect by itself on gene expression in cultured embryonic cortical cells but enhanced the transcriptional response of the cells to CNTF. FGF2 appeared to produce its effects by altering methylation of histones. Although no overall change in histone modification was detected in the cells, histones in the STAT-binding region of a CNTF-responsive gene were modified in a manner that is expected to cause transcriptional activation. Progenitor cells, neurons, and astrocytes analyzed in vivo also showed distinct methylation profiles. In cultured cells, a methyltransferase inhibitor prevented CNTF-dependent activation of transcription. Histone modification also seemed to be sufficient to enhance CNTF signaling, as overexpression of a methyltransferase increased CNTF-dependent transcriptional activation. The authors propose that such growth factor-induced chromatin remodeling may provide a general mechanism for epigenetic regulation of gene expression during development.

M.-R. Song, A. Ghosh, FGF2-induced chromatin remodeling regulates CNTF-mediated gene expression and astrocyte differentiation. Nat. Neurosci. 7, 229-235 (2004). [Online Journal]