ABSTRACT
Bromodomain-containing protein 2 (Brd2) is a BET family chromatin adaptor required for expression of cell-cycle-associated genes and therefore involved in cell cycle progression. Brd2 is expressed in proliferating neuronal progenitors, displays cell-cycle-stimulating activity and, when overexpressed, impairs neuronal differentiation. Paradoxically, Brd2 is also detected in differentiating neurons. To shed light on the role of Brd2 in the transition from cell proliferation to differentiation, we had previously looked for proteins that interacted with Brd2 upon induction of neuronal differentiation. Surprisingly, we identified the growth factor pleiotrophin (Ptn). Here, we show that Ptn antagonized the cell-cycle-stimulating activity associated with Brd2, thus enhancing induced neuronal differentiation. Moreover, Ptn knockdown reduced neuronal differentiation. We analyzed Ptn-mediated antagonism of Brd2 in a cell differentiation model and in two embryonic processes associated with the neural tube: spinal cord neurogenesis and neural crest migration. Finally, we investigated the mechanisms of Ptn-mediated antagonism and determined that Ptn destabilizes the association of Brd2 with chromatin. Thus, Ptn-mediated Brd2 antagonism emerges as a modulation system accounting for the balance between cell proliferation and differentiation in the vertebrate nervous system.
Footnotes
Competing interests
The authors declare no competing interests.
Author contributions
P.G.-G. designed and performed experiments, F.J.-V. performed experiments, D.J.W. designed experiments and corrected the manuscript, M.G.-D. conceived the project, designed and performed experiments and wrote the manuscript.
Funding
This work was supported by the Ministry of Economy and Competitiveness (MINECO) [grant number BFU2012-37304 to M.G.-D.]; the National Institutes of Health [grant numbers GM081767 and NS052482 to D.J.W.]. P.G.-G. and F.J.-V. were the recipients of JAE PhD fellowships from Consejo Superior de Investigaciones Cientificas (CSIC). Deposited in PMC for release after 12 months.
- Received December 3, 2013.
- Accepted March 17, 2014.
- © 2014. Published by The Company of Biologists Ltd