TY - JOUR
T1 - Pumilio2 regulates synaptic plasticity via translational repression of synaptic receptors in mice
AU - Dong, Hongxin
AU - Zhu, Mengyi
AU - Meng, Liping
AU - Ding, Yan
AU - Yang, Ding
AU - Zhang, Shanshan
AU - Qiang, Wenan
AU - Fisher, Daniel W.
AU - Xu, Eugene Yujun
N1 - Funding Information:
We would like to thank Yang Yang and Geethi Abraham for technical help. We also acknowledge the Welcome Trust Sanger Institute and Feinberg school of Medicine Transgenic core facility (TTML) for their help with transgenic mouse generation. This work was supported by National Basic Research Program of China (973 program, 2013CB945201 and 2015CB943002); National Science Foundation of China (81270737 and 31771652); Natural Science Foundation of Jiangsu Province (BK2012838); Provincial Innovation and Entrepreneurship Grant as well as NIH grant U01 HD045871. Funding for open access charge: Provincial Shuangchuan Program. W. Qiang was partially supported by NU-PSOC (U54 CA193419) and Robert H. Lurie Comprehensive Cancer Center OncoSET initiatives at the Northwestern University. This work is partially supported by the National Institute of Mental Health (R21 MH100919-01A1, 5R01 MH109466-2) to Hongxin Dong.
Publisher Copyright:
© Dong et al.
PY - 2018/8/14
Y1 - 2018/8/14
N2 - 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.
AB - 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.
KW - Dendrite
KW - Glutamate receptor 2 (GLUR2)
KW - Pumilio (PUM)
KW - RNA binding protein
KW - Synapse
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U2 - 10.18632/oncotarget.24345
DO - 10.18632/oncotarget.24345
M3 - Article
C2 - 30181804
AN - SCOPUS:85051603554
VL - 9
SP - 32134
EP - 32148
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 63
ER -