Pleiotrophin antagonizes Brd2 during neuronal differentiation.
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.
Stem Cells Department, Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER) (Consejo Superior de Investigaciones Cientificas (CSIC), Junta de Andalucía, Universidad de Sevilla, Universidad Pablo de Olavide), Seville 41092, Spain.
Pablo
P
Garcia-Gutierrez
Stem Cells Department, Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER) (Consejo Superior de Investigaciones Cientificas (CSIC), Junta de Andalucía, Universidad de Sevilla, Universidad Pablo de Olavide), Seville 41092, Spain.
Francisco
F
Juarez-Vicente
Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA.
Debra J
DJ
Wolgemuth
Stem Cells Department, Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER) (Consejo Superior de Investigaciones Cientificas (CSIC), Junta de Andalucía, Universidad de Sevilla, Universidad Pablo de Olavide), Seville 41092, Spain mario.garcia@cabimer.es.
Mario
M
Garcia-Dominguez
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002843:Chromatin / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009432:Neural Crest / Q000502:physiology*; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000502:physiology*; D011485:Protein Binding / Q000235:genetics; D015202:Protein Engineering; D034741:RNA, Small Interfering / Q000235:genetics; D013116:Spinal Cord / Q000502:physiology*; D014157:Transcription Factors; D000092468:Bromodomain Containing Proteins
D002352:Carrier Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D016207:Cytokines; D034741:RNA, Small Interfering; D014157:Transcription Factors; C490844:Brd2 protein, mouse; D000092468:Bromodomain Containing Proteins; C066845:pleiotrophin
Brd2; Chromatin; Neuronal differentiation; Ptn