University of Massachusetts Medical School Faculty Publications

UMMS Affiliation

Department of Microbiology and Physiological Systems; Program in Neuroscience

Publication Date


Document Type



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


Amino Acids, Peptides, and Proteins | Enzymes and Coenzymes | Genetic Phenomena | Molecular and Cellular Neuroscience | Nervous System | Neuroscience and Neurobiology


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

Publisher PDF posted as allowed by the publisher's author rights policy at

DOI of Published Version



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

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

The Journal of neuroscience : the official journal of the Society for Neuroscience

PubMed ID