Abstract
BackgroundExtracellular signaling through receptors for neurotrophins mediates diverse neuronal functions, including survival, migration and differentiation in the central nervous system, but the transcriptional targets and regulators that mediate these diverse neurotrophin functions are not well understood.ResultsWe have identified the immediate-early (IE) genes Fos, Egr1 and Egr2 as transcriptional targets of brain derived neurotrophic factor (BDNF)/TrkB signaling in primary cortical neurons, and show that the Fos serum response element area responds to BDNF/TrkB in a manner dependent on a combined C/EBP-Ebox element. The Egr1 and Egr2 promoters contain homologous regulatory elements. We found that C/EBPα/β and NeuroD formed complexes in vitro and in vivo, and were recruited to all three homologous promoter regions. C/EBPα and NeuroD co-operatively activated the Fos promoter in transfection assays. Genetic depletion of Trk receptors led to impaired recruitment of C/EBPs and NeuroD in vivo, and elimination of Cebpa and Cebpb alleles reduced BDNF induction of Fos, Egr1 and Egr2 in primary neurons. Finally, defective differentiation of cortical dendrites, as measured by MAP2 staining, was observed in both compound Cebp and Ntrk knockout mice.ConclusionWe here identify three IE genes as targets for BDNF/TrkB signaling, show that C/EBPα and -β are recruited along with NeuroD to target promoters, and that C/EBPs are essential mediators of Trk signaling in cortical neurons. We show also that C/EBPs and Trks are required for cortical dendrite differentiation, consistent with Trks regulating dendritic differentiation via a C/EBP-dependent mechanism. Finally, this study indicates that BDNF induction of IE genes important for neuronal function depends on transcription factors (C/EBP, NeuroD) up-regulated during neuronal development, thereby coupling the functional competence of the neuronal cells to their differentiation.
Highlights
Extracellular signaling through receptors for neurotrophins mediates diverse neuronal functions, including survival, migration and differentiation in the central nervous system, but the transcriptional targets and regulators that mediate these diverse neurotrophin functions are not well understood
Brain derived neurotrophic factor (BDNF) induces Egr1, Egr2 and Fos expression in primary cortical neurons To identify genes regulated by BDNF signaling through TrkB in neuronal cells, primary cortical neurons derived from E15.5 embryonic forebrain were stimulated with BDNF and their gene expression compared to that of untreated control cultures by microarray analysis
Among the most highly regulated genes was a group encoding immediate-early (IE) transcription factors that consisted of Egr1, Egr2 and Fos
Summary
Extracellular signaling through receptors for neurotrophins mediates diverse neuronal functions, including survival, migration and differentiation in the central nervous system, but the transcriptional targets and regulators that mediate these diverse neurotrophin functions are not well understood. NeuroD selectively promotes dendrite, but not axonal, morphogenesis in granule neurons through its phosphorylation at distinct sites by CamKII [8] These factors form heterodimers with ubiquitously expressed bHLH proteins, such as E12 and E47, and activate gene expression programs through interaction, via their basic domain, with DNA sequences containing the core hexanucleotide motif CANNTG, known as the Ebox [9,10]. It is still unknown which extracellular signals or intracellular mechanisms are involved in the regulation of bHLH factor function
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