Palladin Is a Neuron-Specific Translational Target of mTOR Signaling That Regulates Axon Morphogenesis.

Abstract

The mTOR signaling pathway regulates protein synthesis and diverse aspects of neuronal morphology that are important for brain development and function. To identify proteins controlled translationally by mTOR signaling, we performed ribosome profiling analyses in mouse cortical neurons and embryonic stem cells upon acute mTOR inhibition. Among proteins whose translation was significantly affected by mTOR inhibition selectively in neurons, we identified the cytoskeletal regulator protein palladin, which is localized within the cell body and axons in hippocampal neurons. Knockdown of palladin eliminated supernumerary axons induced by suppression of the tuberous sclerosis complex protein TSC1 in neurons, demonstrating that palladin regulates neuronal morphogenesis downstream of mTOR signaling. Our findings provide novel insights into an mTOR-dependent mechanism that controls neuronal morphogenesis through translational regulation.SIGNIFICANCE STATEMENT This study reports the discovery of neuron-specific protein translational responses to alterations of mTOR activity. By using ribosome profiling analysis, which can reveal the location and quantity of translating ribosomes on mRNAs, multiple aspects of protein translation were quantitatively analyzed in mouse embryonic stem cells and cortical neurons upon acute mTOR inhibition. Neurons displayed distinct patterns of ribosome occupancy for each codon and ribosome stalling during translation at specific positions of mRNAs. Importantly, the cytoskeletal regulator palladin was identified as a translational target protein of mTOR signaling in neurons. Palladin operates downstream of mTOR to modulate axon morphogenesis. This study identifies a novel mechanism of neuronal morphogenesis regulated by mTOR signaling through control of translation of the key protein palladin.

• Authors: Yusuke Umegaki, Antonio Martínez Brotons, Yui Nakanishi, Zhongyue Luo, Hanlu Zhang, Azad Bonni, Yoshiho Ikeuchi
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 38 Issue 21 Pg. 4985-4995 (05 23 2018) ISSN: 1529-2401 [Electronic] United States
• PMID: 29712777 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 the authors 0270-6474/18/384985-11$15.00/0.

Chemical References

• Cytoskeletal Proteins
• Phosphoproteins
• Tsc1 protein, mouse
• Tuberous Sclerosis Complex 1 Protein
• palladin protein, mouse
• mTOR protein, mouse
• TOR Serine-Threonine Kinases

Topics

• Animals
• Axons (physiology)
• Cells, Cultured
• Cytoskeletal Proteins (genetics, physiology)
• Female
• Gene Knockdown Techniques
• Male
• Mice
• Mice, Inbred ICR
• Morphogenesis (genetics, physiology)
• Phosphoproteins (genetics, physiology)
• Protein Biosynthesis
• RNA Editing
• Ribosomes (chemistry, genetics)
• Signal Transduction (physiology)
• TOR Serine-Threonine Kinases (genetics, physiology)
• Tuberous Sclerosis Complex 1 Protein (metabolism)