Growing Long Distance - RNA Control of Neuronal Extension

Introduction

Neurons are the longest cells, extending axons over distances that can reach four orders of magnitude larger than their cell body diameters. How can they achieve such long distance growth? After initial engagement with target cells, neurons undergo stretch-induced elongation as the nervous system matures with the growth of the organism. The molecular mechanisms enabling such prodigious growth are unknown.

Hypothesis

Based on strong preliminary evidence, we tested the hypothesis that both the initial elongating and later stretch-induced axon growth act via a shared RNA localization mechanism.

Key Findings

Very strikingly, we identified a specific subset of polyadenylated repeat element RNAs, hereby termed growth-inducing SINEs (GI-SINEs), as key growth regulators.

1. GI-SINEs are induced from AP-1 promoter-associated extragenic loci.
2. They interact with ribosomal proteins and the axon growth regulating RNA binding protein nucleolin in neuronal cytoplasm.

Research Objectives

We will elucidate how this intrinsic mechanism controls neuron growth by determining:

1. How known elongating growth regulators affect stretch-induced growth.
2. How local and global protein synthesis regulate neuron growth control.
3. How growth regulates the GI-SINEs and how they regulate different growth modalities.

Methodology

We will apply a multidisciplinary suite of techniques and approaches to these challenges, including a new technology for characterization of nascent proteomes developed in-house.

Impact

The proposed project will provide ground-breaking and fundamental mechanistic insights on neuronal growth and will establish novel methods that will be widely applicable. Moreover, establishing that a repeat element RNA is an intrinsic effector linking AP-1 transcription to translation regulation is a breakthrough finding that opens new horizons for cell biology and neuroscience.