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Temporal regulation of nuclear factor one occupancy by calcineurin/NFAT governs a voltage-sensitive developmental switch in late maturing neurons
Authors
Ding, BaojinWang, Wei
Selvakumar, Tharakeswari
Xi, Hualin Simon
Zhu, Hong
Chow, Chi-Wing
Horton, Jay D.
Gronostajski, Richard M.
Kilpatrick, Daniel L.
Student Authors
Wei WangAcademic Program
Bioinformatics and Computational BiologyUMass Chan Affiliations
Morningside Graduate School of Biomedical SciencesMicrobiology and Physiological Systems
Document Type
Journal ArticlePublication Date
2013-02-13
Metadata
Show full item recordAbstract
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.Source
J Neurosci. 2013 Feb 13;33(7):2860-72. doi: 10.1523/JNEUROSCI.3533-12.2013. Link to article on publisher's site
DOI
10.1523/JNEUROSCI.3533-12.2013Permanent Link to this Item
http://hdl.handle.net/20.500.14038/29633PubMed ID
23407945Related Resources
Rights
Publisher PDF posted as allowed by the publisher's author rights policy at http://www.jneurosci.org/site/misc/ifa_policies.xhtml#copyright.ae974a485f413a2113503eed53cd6c53
10.1523/JNEUROSCI.3533-12.2013