Exploring the role of p53 in synapse development and elimination

项目摘要/摘要 突触在我们的神经系统中调节神经传递。虽然促进或稳定了 突触连接促进信号传递，突触消除对塑造大脑电路至关重要 发展，但人们对此知之甚少。在自闭症谱系障碍(ASD)中，突触消除受损 被观察到并被认为是ASD患者认知缺陷的部分基础。人们普遍认为 基因转录激活是消除突触所必需的。然而，参与转录的 影响因素和潜在的分子机制仍然难以捉摸。我们最近的研究表明，这种活动-- 通过肌细胞增强因子2(MEF2)消除依赖突触需要去磷酸化 泛素E3连接酶小鼠双分钟-2(MDM2)(Tsai等人，2017年)。我们的最新数据显示， 肿瘤抑制因子P53的泛素化及对肿瘤抑制因子P53活性的影响 MEF2激活。这一观察表明，P53介导的基因转录可能在活性中发挥作用- 依赖性突触消除。因为我们还观察到两个ASD小鼠的P53泛素化水平升高 在已知突触数量增加的模型中，我们建议检验一种假设，即p53介导 在发育过程中和神经元活动刺激时突触的消除，以及这种异常减少 自闭症患者突触数目增加与P53活性有关。在目标1中，我们将确定P53在 突触发育。在目标2中，我们将探讨MEF2和P53在突触消除中的相互作用。在……里面 目的3我们将确定P53泛素化升高在两个ASD突触数量增加中的作用。 老鼠模型。由于癌症生物学领域对P53的广泛了解，我们预计 研究迅速为神经遗传学和突触生物学的研究开辟了一条新的途径。此外， 由于许多与p53相关的药物都可以在临床上使用，我们研究的数据可以让基础研究人员 和临床医生在自闭症和其他神经发育疾病的研究中迅速取得进展。

PROJECT SUMMARY/ABSTRACT Synapses mediate neurotransmission in our nervous systems. Although facilitation or stabilization of synaptic connections promotes signal transmission, synaptic elimination is vital to shaping the brain circuit during development, but is less understood. In autism spectrum disorders (ASDs), impaired synapse elimination has been observed and implicated to underlie parts of the cognitive deficits in ASD patients. It is well accepted that activation of gene transcription is required for synaptic elimination. However, the participating transcription factors and underlying molecular mechanisms remain elusive. Our recent work demonstrated that activity- dependent synapse elimination through myocyte enhanced factor 2 (MEF2) requires dephosphorylation of ubiquitin E3 ligase murine double minute-2 (Mdm2) (Tsai et al., 2017). Our latest data showed a reduction of ubiquitination of tumor suppressor p53, one of the Mdm2’s substrates, and an elevation of p53 activity upon MEF2 activation. This observation indicates a possible role of p53-mediated gene transcription in activity- dependent synapse elimination. Because we also observed elevated p53 ubiquitination in two ASD mouse models in which synapse number is known to be elevated, we propose to test a hypothesis that p53 mediates synapse elimination during development and upon neuronal activity stimulation, and that abnormally reduced p53 activity contributes to elevated synapse numbers in ASDs. In Aim 1 we will determine the role of p53 in synapse development. In Aim 2 we will explore the interplay between MEF2 and p53 in synapse elimination. In Aim 3 we will determine the contribution of elevated p53 ubiquitination in elevated synapse number in two ASD mouse models. Because of the extensive understanding of p53 within the field of cancer biology, we expect this research to quickly open a new avenue for the study of neurogenetics and synaptic biology. Furthermore, because many drugs related to p53 are clinically available, data from our research could allow basic researchers and clinicians to make rapid gains in the study of ASDs and other neurodevelopmental diseases.