University of Massachusetts Medical School Faculty Publications

UMMS Affiliation

Department of Microbiology and Physiological Systems; Program in Neuroscience

Date

2-13-2013

Document Type

Article

Medical Subject Headings

Animals; Calcineurin; Calcium Channels, L-Type; Cell Differentiation; Cell Line; Chromatin Immunoprecipitation; Computational Biology; Cytoplasm; Dendrites; Female; Fluorescent Antibody Technique; Genetic Vectors; Lentivirus; Male; Membrane Potentials; Mice; Microarray Analysis; NFATC Transcription Factors; NFI Transcription Factors; Neurons; Plasmids; T-Lymphocytes; Voltage-Sensitive Dye Imaging

Disciplines

Molecular and Cellular Neuroscience | Neuroscience and Neurobiology

Abstract

Dendrite and synapse development are critical for establishing appropriate neuronal circuits, and disrupted timing of these events can alter neural connectivity. Using microarrays, we have identified a nuclear factor I (NFI)-regulated temporal switch program linked to dendrite formation in developing mouse cerebellar granule neurons (CGNs). NFI function was required for upregulation of many synapse-related genes as well as downregulation of genes expressed in immature CGNs. Chromatin immunoprecipitation analysis revealed that a central feature of this program was temporally regulated NFI occupancy of late-expressed gene promoters. Developing CGNs undergo a hyperpolarizing shift in membrane potential, and depolarization inhibits their dendritic and synaptic maturation via activation of calcineurin (CaN) (Okazawa et al., 2009). Maintaining immature CGNs in a depolarized state blocked NFI temporal occupancy of late-expressed genes and the NFI switch program via activation of the CaN/nuclear factor of activated T-cells, cytoplasmic (NFATc) pathway and promotion of late-gene occupancy by NFATc4, and these mechanisms inhibited dendritogenesis. Conversely, inhibition of the CaN/NFATc pathway in CGNs maturing under physiological nondepolarizing conditions upregulated the NFI switch program, NFI temporal occupancy, and dendrite formation. NFATc4 occupied the promoters of late-expressed NFI program genes in immature mouse cerebellum, and its binding was temporally downregulated with development. Further, NFI temporal binding and switch gene expression were upregulated in the developing cerebellum of Nfatc4 (-/-) mice. These findings define a novel NFI switch and temporal occupancy program that forms a critical link between membrane potential/CaN and dendritic maturation in CGNs. CaN inhibits the program and NFI occupancy in immature CGNs by promoting NFATc4 binding to late-expressed genes. As maturing CGNs become more hyperpolarized, NFATc4 binding declines leading to onset of NFI temporal binding and the NFI switch program.

Rights and Permissions

Citation: J Neurosci. 2013 Feb 13;33(7):2860-72. doi: 10.1523/JNEUROSCI.3533-12.2013. Link to article on publisher's site

Comments

Publisher PDF posted as allowed by the publisher's author rights policy at http://www.jneurosci.org/site/misc/ifa_policies.xhtml#copyright.

Related Resources

Link to Article in PubMed

PubMed ID

23407945

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