DAP5 increases axonal outgrowth of hippocampal neurons by enhancing the cap-independent translation of DSCR1.4 mRNA

Ji-Young Seo,Hye Guk Ryu,Youngseob Jung,Kyong-Tai Kim,Sung Wook Kim,Do-Yeon Kim,Juhyun Lee

doi:10.1038/s41419-018-1299-x

Abstract

Proper wiring between neurons is indispensable for proper brain function. From the early developmental stage, axons grow and navigate to connect to targets according to specific guidance cues. The accuracy of axonal outgrowth and navigation are controlled by a variety of genes, and mutations and/or deficiencies in these genes are closely related to several brain disorders, such as autism. DSCR1 is one of these genes and regulates actin filament formation in axons. Thus, identifying the detailed regulatory mechanisms of DSCR1 expression is crucial for the understanding of the axon development of neurons; however, these regulatory mechanisms of DSCR1 remain unknown. Here, we discovered that mRNA encoding the DSCR1 isoform DSCR1.4 is present and mainly translated by the cap-independent initiation mechanisms in both the soma and axons of hippocampal neurons. We found that translation of DSCR1.4 mRNA is enhanced by death-associated protein 5 (DAP5), which can bind to DSCR1.4 5′UTR. BDNF-stimulus induced an increase in DAP5 expression and the cap-independent translation efficiency of DSCR1.4 mRNA in axon as well as soma. Furthermore, we showed the importance of the cap-independent translation of DSCR1.4 on enhancement of DSCR1.4 expression by BDNF-stimulus and axonal outgrowth of hippocampal neurons. Our findings suggest a new translational regulatory mechanism for DSCR1.4 expressions and a novel function of DAP5 as a positive regulator of DSCR1.4 mRNA translation induced in soma and axon of hippocampal neurons.

Highlights

Down syndrome candidate region 1 (DSCR1), known as regulator of calcineurin 1 (RCAN1) regulates calcineurin and has two major isoforms, isoform 1 (DSCR1.1) and isoform 4 (DSCR1.4)[1]
We hypothesized that capindependent initiation mechanism is involved in DSCR1.4 mRNA translation along with cap-dependent initiation mechanism
As almost all cellular mRNAs regulated by cap-independent mechanisms have cisacting elements in the 5′UTR, we decided to observe the effect of human DSCR1.4 5′-untranslated region (5′-UTR) and mouse DSCR1.4 5′-UTR on the capindependent translation

Summary

Introduction

Down syndrome candidate region 1 (DSCR1), known as regulator of calcineurin 1 (RCAN1) regulates calcineurin and has two major isoforms, isoform 1 (DSCR1.1) and isoform 4 (DSCR1.4)[1]. DSCR1.1 and DSCR1.4 are differentially expressed by alternative promoter usage, leading to differences in both the 5′-untranslated region (5′-UTR) of their mRNAs and the N-terminal domain of the polypeptides. DSCR1 localizes knockout mice have short-axon length. DSCR1 controls local translation in dendritic spines and axon termini[2,3]. Elucidating the regulatory mechanisms of DSCR1 expression in neurons is crucial to understanding normal brain function. Previous studies have described transcriptional and post-translational regulatory mechanisms of DSCR14–6. Most of these studies utilized non-neuronal cells and did not examine the post-transcriptional regulatory mechanisms of DSCR1 mRNA

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Conclusion