University of Massachusetts Medical School Faculty Publications

Title

Dynamics of survival of motor neuron (SMN) protein interaction with the mRNA-binding protein IMP1 facilitates its trafficking into motor neuron axons

UMMS Affiliation

Department of Neurology

Date

3-2014

Document Type

Article

Medical Subject Headings

Animals; Axonal Transport; Axons; Biological Transport, Active; Brain; Cells, Cultured; Chromaffin Granules; Humans; Mice; Mice, Transgenic; Motor Neurons; Protein Interaction Domains and Motifs; RNA-Binding Proteins; Rats; Survival of Motor Neuron 1 Protein; Survival of Motor Neuron 2 Protein

Disciplines

Developmental Biology | Molecular and Cellular Neuroscience | Nervous System Diseases | Neurology | Neuroscience and Neurobiology

Abstract

Spinal muscular atrophy (SMA) is a lethal neurodegenerative disease specifically affecting spinal motor neurons. SMA is caused by the homozygous deletion or mutation of the survival of motor neuron 1 (SMN1) gene. The SMN protein plays an essential role in the assembly of spliceosomal ribonucleoproteins. However, it is still unclear how low levels of the ubiquitously expressed SMN protein lead to the selective degeneration of motor neurons. An additional role for SMN in the regulation of the axonal transport of mRNA-binding proteins (mRBPs) and their target mRNAs has been proposed. Indeed, several mRBPs have been shown to interact with SMN, and the axonal levels of few mRNAs, such as the beta-actin mRNA, are reduced in SMA motor neurons. In this study we have identified the beta-actin mRNA-binding protein IMP1/ZBP1 as a novel SMN-interacting protein. Using a combination of biochemical assays and quantitative imaging techniques in primary motor neurons, we show that IMP1 associates with SMN in individual granules that are actively transported in motor neuron axons. Furthermore, we demonstrate that IMP1 axonal localization depends on SMN levels, and that SMN deficiency in SMA motor neurons leads to a dramatic reduction of IMP1 protein levels. In contrast, no difference in IMP1 protein levels was detected in whole brain lysates from SMA mice, further suggesting neuron specific roles of SMN in IMP1 expression and localization. Taken together, our data support a role for SMN in the regulation of mRNA localization and axonal transport through its interaction with mRBPs such as IMP1.

Rights and Permissions

Citation: Dev Neurobiol. 2014 Mar;74(3):319-32. doi: 10.1002/dneu.22111. Epub 2013 Oct 4. Link to article on publisher's site

Related Resources

Link to Article in PubMed