Etv1/Er81 transcription factor orchestrates activity-dependent gene regulation in the terminal maturation program of cerebellar granule cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 30; pp. 12497 - 12502
• Main Authors: Abe, Haruka, Okazawa, Makoto, Nakanishi, Shigetada
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 26.07.2011; National Acad Sciences
• Subjects: Animals; Biological Sciences; Brain; calcium channels; Cell culture; Cell culture techniques; Cell Differentiation - genetics; Cells, Cultured; Cerebellum; Cerebellum - cytology; Cerebellum - growth & development; Cerebellum - metabolism; Cultured cells; DNA; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; electroporation; Gene expression; gene expression regulation; Gene Expression Regulation, Developmental; Gene Knockdown Techniques; Genes; glutamic acid; luciferase; Messenger RNA; Mice; Models, Neurological; Neurons; Neurosciences; postpartum period; promoter regions; Promoter Regions, Genetic; Purkinje cells; receptors; Receptors, GABA-A - genetics; Receptors, N-Methyl-D-Aspartate - genetics; Signal Transduction; Small interfering RNA; sodium channels; transcription factors; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transcription Factors - metabolism; Up regulation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1109940108

In the postnatal period, cerebellar granule cells express a set of the maturation gene battery in an activity-dependent manner and establish synaptic function in the cerebellar circuitry. Using primary cultures combined with specific inhibition of signaling cascades, the present investigation revealed that the expression of the maturation genes, including the NMDA glutamate receptor NR2C and GABA A receptor GABA A Rα6 genes, is controlled by strikingly unified signaling mechanisms that operate sequentially through stimulation of AMPA and NMDA receptors, Na + channels [voltage-gated Na channel type II (Nav1.2)], and voltage-dependent Ca 2+ channels. This signaling then induces the Ets variant gene 1 (Etv1/Er81) transcription factor of the ETS family in an activity-dependent manner. Consistent with the culture study, the ChIP assay indicated that Etv1 up-regulates the maturation genes in a developmentally regulated manner. This activation, as revealed by the luciferase assay, occurrs by interacting with the Etv1-interacting motifs present in the promoter region. Importantly, in vivo knockdown of Etv1 by DNA electroporation in the developing cerebellum prevents the up-regulation of the maturation genes but has no effects on preceding developmental processes occurring in the granule cells. Etv1 thus orchestrates the activity-dependent gene regulation in the terminal maturation program and specifies the identity of cerebellar granule cells.