Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts, USA; the Cell, Molecular and Developmental Biology Program, Sackler School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, USA.
J Neurochem. 2014 May;129(4):743-52. doi: 10.1111/jnc.12657. Epub 2014 Feb 12.
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.
转录因子功能的调节对神经系统的发育和功能至关重要。转录因子 Sp4 调节树突的发育模式，参与学习和记忆等复杂过程，并与精神分裂症和双相情感障碍等精神疾病有关。尽管 Sp4 在神经系统中有许多作用，但调节其活性的分子机制知之甚少。在这里，我们报告 Sp4 在丝氨酸 770 上的磷酸化位点，该位点在膜去极化时减少。电压依赖性 NMDA 受体的抑制增加了 Sp4 的磷酸化。相反，NMDA 的刺激降低了 Sp4 磷酸化的水平，这依赖于蛋白磷酸酶 1/2A。S770 的磷酸模拟取代会损害小脑颗粒神经元初级树突的 Sp4 依赖性成熟，而不可磷酸化的 Sp4 突变体的行为与野生型相似。这些数据表明，转录因子 Sp4 受 NMDA 受体依赖性蛋白磷酸酶 1/2A 信号通路的激活调节。我们的研究结果还表明，Sp4 活性的调节控制是调节树突发育模式的重要机制。
