Oncotarget

Research Papers:

Pumilio2 regulates synaptic plasticity via translational repression of synaptic receptors in mice

Hongxin Dong, Mengyi Zhu, Liping Meng, Yan Ding, Ding Yang, Shanshan Zhang, Wenan Qiang, Daniel W. Fisher and Eugene Yujun Xu _

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Oncotarget. 2018; 9:32134-32148. https://doi.org/10.18632/oncotarget.24345

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Abstract

Hongxin Dong1, Mengyi Zhu2, Liping Meng1, Yan Ding2, Ding Yang2, Shanshan Zhang1, Wenan Qiang3, Daniel W. Fisher4 and Eugene Yujun Xu2

1Departments of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA

2State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166, P. R. China

3Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA

4Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA

Correspondence to:

Eugene Yujun Xu, email: xuyujun@njmu.edu.cn

Hongxin Dong, email: h-dong@northwestern.edu

Keywords: Pumilio (PUM); RNA binding protein; dendrite; synapse; glutamate receptor 2 (GLUR2)

Received: August 23, 2017     Accepted: January 13, 2018     Epub: January 30, 2018     Published: August 14, 2018

ABSTRACT

PUMILIO 2 (PUM2) is a member of Pumilio and FBF (PUF) family, an RNA binding protein family with phylogenetically conserved roles in germ cell development. The Drosophila Pumilio homolog is also required for dendrite morphogenesis and synaptic function via translational control of synaptic proteins, such as glutamate receptors, and recent mammalian studies demonstrated a similar role in neuronal culture with associated motor and memory abnormalities in vivo. Importantly, transgenic mice with PUM2 knockout show prominent epileptiform activity, and patients with intractable temporal lobe epilepsy and mice with pilocarpine-induced seizures have decreased neuronal PUM2, possibly leading to further seizure susceptibility. However, how PUM2 influences synaptic function in vivo and, subsequently, seizures is not known. We found that PUM2 is highly expressed in the brain, especially in the temporal lobe, and knockout of Pum2 (Pum2–/–) resulted in significantly increased pyramidal cell dendrite spine and synapse density. In addition, multiple proteins associated with excitatory synaptic function, including glutamate receptor 2 (GLUR2), are up-regulated in Pum2–/– mice. The expression of GLUR2 protein but not mRNA is increased in the Pum2–/– mutant hippocampus, Glur2 transcripts are increased in mutant polysome fractions, and overexpression of PUM2 led to repression of reporter expression containing the 3′Untranslated Region (3′UTR) of Glur2, suggesting translation of GLUR2 was increased in the absence of Pum2. Overall, these studies provide a molecular mechanism for the increased temporal lobe excitability observed with PUM2 loss and suggest PUM2 might contribute to intractable temporal lobe epilepsy.


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