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

ABSTRACT: 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?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 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.

SUBMITTER: Abe H

PROVIDER: S-EPMC3145738 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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

Abe Haruka H Okazawa Makoto M Nakanishi Shigetada S

Proceedings of the National Academy of Sciences of the United States of America 20110711 30

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 ...[more]

PMID: 21746923

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Project description:BackgroundAxonal myelination is critical for the functioning of vertebrate nervous system. Myelin sheath malformation or degeneration can cause a variety of neurological diseases. Our previous study identified multiple potential myelination-related transcriptional factors (TFs), including expressed sequence tag (ETS) variant transcription factor 1 (Etv1)/Er81, via gene microarray analysis of Schwann cells (SCs) at various myelination stages. Etv1 is known to be involved in the regulation of neuronal specialization, muscle spindle differentiation, and sensorimotor connectivity. However, to our knowledge, to date, there are no relevant studies that Etv1 regulates SC myelination.MethodsTo investigate the roles of Etv1 in SC re-myelination, an in vivo mouse myelination model was used, in which the sciatic nerve is crushed. Etv1 in nerves was knocked down via in situ injection of cholesterol-modified Etv1-small interfering (si)RNA. The expression of myelin-associated glycoprotein (MAG) was evaluated by Western blotting (WB) and immunohistochemistry (IHC). Myelination was assessed by transmission electron microscopy (TEM). The effects of Etv1 on SC proliferation, migration, and differentiation were assessed in vitro using the EdU cell proliferation kit, a culture-insert scratch assay, a SC aggregate sphere migration assay on the axons of dorsal root ganglions (DRGs), and a SC differentiation model. Chromatin immunoprecipitation (ChIP) united with quantitative real-time PCR (qPCR), known as ChIP-qPCR, and luciferase activity reporter assays were performed to explore the possible mechanisms by which Etv1 controls SC differentiation and myelination.ResultsThe results demonstrated that Etv1 promoted myelination by facilitating SC proliferation, migration, and differentiation. Etv1 expression in SCs was upregulated during re-myelination, and knocking down Etv1 expression dramatically abrogated SC re-myelination in the crushed sciatic nerves. Moreover, silencing of Etv1 by siRNA in SCs in vitro inhibited its migration, proliferation, and differentiation. The results of ChIP-qPCR and luciferase reporter assay showed that Etv1 may regulate SC differentiation and myelination by binding to the promoters of myelination-related genes, such as MAG and Runx2, to initiate their transcription.ConclusionsTaken together, these findings demonstrated a previously unknown role of Etv1 in SC differentiation and myelination, providing a candidate molecular target for clinical interventions in demyelinating diseases.

Dataset Information

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

Publications

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

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