The transcription factor calcium‐response factor limitsNMDAreceptor‐dependent transcription in the developing brain
Copyright policy )The transcription factor calcium‐response factor limitsNMDAreceptor‐dependent transcription in the developing brain
AbstractNeuronal activity sculpts brain development by inducing the transcription of genes such as brain‐derived neurotrophic factor (Bdnf) that modulate the function of synapses. Sensory experience is transduced into changes in gene transcription via the activation of calcium signaling pathways downstream of both L‐type voltage‐gated calcium channels (L‐VGCCs) andNMDA‐type glutamate receptors (NMDARs). These signaling pathways converge on the regulation of transcription factors including calcium‐response factor (CaRF). Although CaRFis dispensable for the transcriptional induction ofBdnffollowing the activation of L‐VGCCs, here we show that the loss of CaRFleads to enhancedNMDAR‐dependent transcription ofBdnfas well asArc. We identify theNMDARsubunit‐encoding geneGrin3aas a regulatory target of CaRF, and we show that expression of bothCarfandGrin3ais depressed by the elevation of intracellular calcium, linking the function of this transcriptional regulatory pathway to neuronal activity. We find that light‐dependent activation ofBdnfandArctranscription is enhanced in the visual cortex of young CaRFknockout mice, suggesting a role for CaRF‐dependent dampening ofNMDAR‐dependent transcription in the developing brain. Finally, we demonstrate that enhancedBdnfexpression in CaRF‐lacking neurons increases inhibitory synapse formation. Taken together, these data reveal a novel role for CaRFas an upstream regulator ofNMDAR‐dependent gene transcription and synapse formation in the developing brain.imageNMDARs promote brain development by inducing the transcription of genes, including brain‐derived neurotrophic factor (BDNF). We show that the transcription factor calcium‐response factor (CaRF) limits NMDAR‐dependent BDNF induction by regulating expression of the NMDAR subunit GluN3A. Loss of CaRF leads to enhanced BDNF‐dependent GABAergic synapse formation indicating the importance of this process for brain development. Our observation that both CaRF and GluN3A are down‐regulated by intracellular calcium suggests that this may be a mechanism for experience‐dependent modulation of synapse formation.
- Duke University United States
- Duke Medical Center United States
Cerebral Cortex, Male, Neurons, Membrane Glycoproteins, Brain-Derived Neurotrophic Factor, Brain, Gene Expression Regulation, Developmental, Mice, Transgenic, Tetrodotoxin, Calcium Channel Blockers, Embryo, Mammalian, Mice, Inbred C57BL, Disease Models, Animal, Mice, Animals, Newborn, Animals, Female, Excitatory Amino Acid Antagonists, Cells, Cultured, Transcription Factors
Cerebral Cortex, Male, Neurons, Membrane Glycoproteins, Brain-Derived Neurotrophic Factor, Brain, Gene Expression Regulation, Developmental, Mice, Transgenic, Tetrodotoxin, Calcium Channel Blockers, Embryo, Mammalian, Mice, Inbred C57BL, Disease Models, Animal, Mice, Animals, Newborn, Animals, Female, Excitatory Amino Acid Antagonists, Cells, Cultured, Transcription Factors
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