Mammalian Pumilio 2 regulates dendrite morphogenesis and synaptic function

Abstract

In Drosophila, Pumilio (Pum) is important for neuronal homeostasis as well as learning and memory. We have recently characterized a mammalian homolog of Pum, Pum2, which is found in discrete RNAcontaining particles in the somatodendritic compartment of polarized neurons. In this study, we investigated the role of Pum2 in developing and mature neurons by RNA interference. In immature neurons, loss of Pum2 led to enhanced dendritic outgrowth and arborization. In mature neurons, Pum2 down-regulation resulted in a significant reduction in dendritic spines and an increase in elongated dendritic filopodia. Furthermore, we observed an increase in excitatory synapse markers along dendritic shafts. Electrophysiological analysis of synaptic function of neurons lacking Pum2 revealed an increased miniature excitatory postsynaptic current frequency. We then identified two specific mRNAs coding for a known translational regulator, eIF4E, and for a voltage-gated sodium channel, Scn1a, which interacts with Pum2 in immunoprecipitations from brain lysates. Finally, we show that Pum2 regulates translation of the eIF4E mRNA. Taken together, our data reveal a previously undescribed role for Pum2 in dendrite morphogenesis, synapse function, and translational control.

BDNF-induced local protein synthesis and synaptic plasticity

“…Accordingly, neurons lacking Pum2 show enhanced dendritic arborization (Vessey et al, 2010). Pum2 is an RNA-binding protein present in discrete RNAcontaining particles, which negatively regulates eIF4E translation (Vessey et al, 2010). Interestingly, loss of Pumilio impairs long-term memory in Drosophila (Dubnau et al, 2003).…”

“…BDNF and synaptic activity were shown to increase the transcription of miR-134, which was coupled to the downregulation of Pumilio2 (Pum2) mRNA to promote dendritogenesis in hippocampal neurons (Fiore et al, 2009). Accordingly, neurons lacking Pum2 show enhanced dendritic arborization (Vessey et al, 2010). Pum2 is an RNA-binding protein present in discrete RNAcontaining particles, which negatively regulates eIF4E translation (Vessey et al, 2010).…”

Pumilio Puf domain RNA-binding proteins in Arabidopsis

“…It is also possible that APUM23 interacts with translation initiation factors, such as eIF-4E, and mediates translation control, as do mammalian Puf proteins, 28 or it may bind to the 3'UTR of eIF-4E mRNA to control its translation. 26,27 The increased sensitivity of apum23-1 to cycloheximide, a eukaryotic protein synthesis inhibitor and its resistance to the antibiotic streptomycin, argue in favor of the involvement of APUM23 in the control of translation and ribosome biogenesis. Ribosomal proteins and rRNA together constitute the structural components of the ribosomes.…”

“…For example, Drosophila Pum and mammalian Pumilio 2 proteins control the abundance of eIF-4E mRNA by binding its 3'UTR and mediating its decay. 26,27 However, recently mammalian Pumilio 2 was shown to interfere with translation control through a non-decay pathway by competing with eIF-4E protein for access to the 7-methyl guanosine cap and repressing the initiation of translation by outcompeting eIF-4E, thereby preventing formation of the initiation complex. 28 Hence, certain Pumilio proteins appear to play a role in the initiation of translation by controlling eIF-4E.…”

Translational Regulation of Acetylcholinesterase by the RNA-binding Protein Pumilio-2 at the Neuromuscular Synapse

“…In Drosophila, Pumilio is required for development and differentiation of the glutaminergic neuromuscular synapse where it also regulates expression of the receptors (20). In the Drosophila CNS, Pumilio is expressed in the mushroom bodies where it is essential for memory and learning (21), and in mice, Pumilio is necessary for dendrite development and differentiation (22). The unifying thought is that Pumilio is essential for synapse formation and maintenance in many species.…”