Pleiotrophin antagonizes Bromodomain-containing protein 2 (Brd2) during neuronal differentiation

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 have looked for Brd2 interacting proteins upon induction of neuronal differentiation. Surprisingly, we have identified the growth factor Pleiotrophin (Ptn). Ptn antagonizes the cell cycle-stimulating activity associated with Brd2, thus enhancing induced neuronal differentiation. Moreover, Ptn knockdown reduces neuronal differentiation. Ptn-mediated antagonism of Brd2 has been assessed in a cell differentiation model and in two embryonic processes associated with the neural tube: spinal cord neurogenesis and neural crest migration. Finally we have investigated the mechanisms of Ptn-mediated antagonism and determined that Ptn destabilizes Brd2 association with chromatin. Thus, Ptn-Brd2 antagonism emerges as a modulation system accounting for the balance between cell proliferation and differentiation in the vertebrate nervous system.