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.
Highlights
Increasing evidence is implicating synaptic dysfunction in temporal lobe structures, especially the hippocampus, as being causally important to many neuropsychiatric disorders, such as epilepsy, Post Traumatic Stress Disorder (PTSD), schizophrenia, and Alzheimer’s Disease (AD) [1,2,3,4,5,6,7]
The expression of glutamate receptor 2 (GLUR2) protein but not mRNA is increased in the Pum2–/– mutant hippocampus, Glur2 transcripts are increased in mutant polysome fractions, and overexpression of PUMILIO 2 (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
PUM2 binds to specific RNA sequences known as Nanos response elements (NREs), called Pumilio Binding Element (PBE) [12, 15, 17, 18], and PUM2 may be highly regulated by the Noncoding RNA activated by DNA damage (NORAD) [19, 20]
Summary
Increasing evidence is implicating synaptic dysfunction in temporal lobe structures, especially the hippocampus, as being causally important to many neuropsychiatric disorders, such as epilepsy, Post Traumatic Stress Disorder (PTSD), schizophrenia, and Alzheimer’s Disease (AD) [1,2,3,4,5,6,7]. Though many molecular modifications are likely to account for these disease states, posttranscriptional regulation of local mRNA at synapses has emerged as a key mechanism controlling synaptic plasticity and dendrite morphogenesis in both health and disease [8, 9]. Often, these local post-transcriptional mechanisms rely on RNA-binding proteins (RBP), but detailed accounts of how these proteins affect synaptogenesis are in their infancy. PUM proteins bind to the 3′ Untranslated region (3′ UTR) of their target mRNAs, likely halting translation until certain synaptic signals are presented [11, 15, 16]. PUM2 binds to specific RNA sequences known as Nanos response elements (NREs), called Pumilio Binding Element (PBE) [12, 15, 17, 18], and PUM2 may be highly regulated by the Noncoding RNA activated by DNA damage (NORAD) [19, 20]
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