Phosphorylation of the transcription factor Sp4 is reduced by NMDA receptor signaling

Authors

  • Gregory Saia,

    1. Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts, USA
    2. the Cell, Molecular and Developmental Biology Program, Sackler School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, USA
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  • Jasmin Lalonde,

    1. Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts, USA
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  • Xinxin Sun,

    1. Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts, USA
    2. Genetics Program, Sackler School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, USA
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  • Belén Ramos,

    1. Unitat de recerca, Parc Sanitari Sant Joan de Déu, Fundació Sant Joan de Déu, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Barcelona, Spain
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  • Grace Gill

    Corresponding author
    1. Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts, USA
    • Address correspondence and reprint requests to Grace Gill, Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA. E-mail: Grace.Gill@tufts.edu

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Abstract

The regulation of transcription factor function in response to neuronal activity is important for development and function of the nervous system. The transcription factor Sp4 regulates the developmental patterning of dendrites, contributes to complex processes including learning and memory, and has been linked to psychiatric disorders such as schizophrenia and bipolar disorder. Despite its many roles in the nervous system, the molecular mechanisms regulating Sp4 activity are poorly understood. Here, we report a site of phosphorylation on Sp4 at serine 770 that is decreased in response to membrane depolarization. Inhibition of the voltage-dependent NMDA receptor increased Sp4 phosphorylation. Conversely, stimulation with NMDA reduced the levels of Sp4 phosphorylation, and this was dependent on the protein phosphatase 1/2A. A phosphomimetic substitution at S770 impaired the Sp4-dependent maturation of cerebellar granule neuron primary dendrites, whereas a non-phosphorylatable Sp4 mutant behaved like wild type. These data reveal that transcription factor Sp4 is regulated by NMDA receptor-dependent activation of a protein phosphatase 1/2A signaling pathway. Our findings also suggest that the regulated control of Sp4 activity is an important mechanism governing the developmental patterning of dendrites.

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We show that the neuronal transcription factor Sp4, which regulates the developmental patterning of dendrites, is dephosphorylated at S770 in response to NMDA receptor signaling in cerebellar granule neurons and cortical neurons. Dephosphorylation required the activity of the PP1/PP2A phosphatase. A point mutation at S770 to a phosphomimetic aspartic acid residue impaired Sp4-dependent pruning of cerebellar granule neuron primary dendrites.

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