The spliceosome-associated protein Mfap1 binds to VCP in Drosophila.

Sandra Rode,Jaqueline Zipfel,Sebastian Rumpf,Henrike Ohm,Brian D Mccabe

doi:10.1371/journal.pone.0183733

Abstract

Posttranscriptional regulation of gene expression contributes to many developmental transitions. Previously, we found that the AAA chaperone Valosin-Containing Protein (VCP) regulates ecdysone-dependent dendrite pruning of Drosophila class IV dendritic arborization (c4da) neurons via an effect on RNA metabolism. In a search for RNA binding proteins associated with VCP, we identified the spliceosome-associated protein Mfap1, a component of the tri-snRNP complex. Mfap1 is a nucleolar protein in neurons and its levels are regulated by VCP. Mfap1 binds to VCP and TDP-43, a disease-associated RNA-binding protein. via distinct regions in its N- and C-terminal halfs. Similar to vcp mutations, Mfap1 overexpression causes c4da neuron dendrite pruning defects and mislocalization of TDP-43 in these cells, but genetic analyses show that Mfap1 is not a crucial VCP target during dendrite pruning. Finally, rescue experiments with a lethal mfap1 mutant show that the VCP binding region is not essential for Mfap1 function, but may act to increase its stability or activity.

Highlights

Pruning, the regulated loss of synapses or neurites during neuronal development, is an important specification mechanism that contributes to the mature morphology of neurons [1]
We previously found that mutations in the ubiquitin-proteasome system (UPS) chaperone Valosin-Containing Protein (VCP, known as TER94), cause defects in dendrite pruning and ecdysone-induced neuronal apoptosis [8,9]
Based on our previous analysis of the role of VCP during c4da neuron dendrite pruning [8], we hypothesized that VCP might be involved in the inactivation of target RNA binding proteins (RBPs)

Summary

Introduction

The regulated loss of synapses or neurites during neuronal development, is an important specification mechanism that contributes to the mature morphology of neurons [1]. C4da neuron dendrite pruning is regulated by the steroid hormone ecdysone [2,3]. Ecdysone activates the EcR-B1 isoform of the ecdysone receptor, a transcription factor of the steroid hormone receptor type, leading to the expression of pruning genes such as Sox, Mical, and headcase [4,5]. These gene expression changes result in destabilization of dendritic microtubules and the dendritic plasma membrane [6,7] In addition, the ubiquitin-proteasome system (UPS) is required for dendrite pruning [2].

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Conclusion