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First published online 15 June 2005
doi: 10.1242/dev.01893

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SMAD pathway mediation of BDNF and TGFß2 regulation of proliferation and differentiation of hippocampal granule neurons

¹ NeuroAdaptations Group, Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, D-80804 Munich, Germany
² Neuroscience Group, Life and Health Sciences Research Institute (ICVS), University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal

^* Author for correspondence (e-mail: osa{at}mpipsykl.mpg.de)

Accepted 9 May 2005

Hippocampal granule cells self-renew throughout life, whereas their cerebellar counterparts become post-mitotic during early postnatal development, suggesting that locally acting, tissue-specific factors may regulate the proliferative potential of each cell type. Confirming this, we show that conditioned medium from hippocampal cells (CM_Hippocampus) stimulates proliferation in cerebellar cultures and, vice versa, that mitosis in hippocampal cells is inhibited by CM_Cerebellum. The anti-proliferative effects of CM_Cerebellum were accompanied by increased expression of the cyclin-dependent kinase inhibitors p21 and p27, as well as markers of neuronal maturity/differentiation. CM_Cerebellum was found to contain peptide-like factors with distinct anti-proliferative/differentiating and neuroprotective activities with differing chromatographic properties. Preadsorption of CM_Cerebellum with antisera against candidate cytokines showed that TGFß2 and BDNF could account for the major part of the anti-proliferative and pro-differentiating activities, an interpretation strengthened by studies involving treatment with purified TGFß2 and BDNF. Interference with signaling pathways downstream of TGFß and BDNF using dominant-negative forms of their respective receptors (TGFß2-RII and TRKB) or of dominant-negative forms of SMAD3 and co-SMAD4 negated the anti-proliferative/differentiating actions of CM_Cerebellum. Treatment with CM_Cerebellum caused nuclear translocation of SMAD2 and SMAD4, and also transactivated a TGFß2-responsive gene. BDNF actions were shown to depend on activation of ERK1/2 and to converge on the SMAD signaling cascade, possibly after stimulation of TGFß2 synthesis/secretion. In conclusion, our results show that the regulation of hippocampal cell fate in vitro is regulated through an interplay between the actions of BDNF and TGFß.

Key words: Neurogenesis, Apoptosis, Neuronal differentiation, Hippocampus, Cerebellum, TGFß2, BDNF, SMAD, Rat

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