Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 30, Pages 12497-12502Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1109940108
Keywords
cell culture; membrane potential; neuronal cell excitation; synaptic maturation; transcriptional regulation
Categories
Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [KAKENHI 22220005, 21790294]
- Japan Society for the Promotion of Science
- Takeda Science Foundation
- Suntory Institute for Bioorganic Research
- Grants-in-Aid for Scientific Research [22220005, 21790294] Funding Source: KAKEN
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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)R alpha 6 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 Ca2+ 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.
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