Local synthesis of dynein cofactors matches retrograde transport to acutely changing demands

• Published in: Nature communications Vol. 7; no. 1; p. 13865
• Main Authors: Villarin, Joseph M., McCurdy, Ethan P., Martínez, José C., Hengst, Ulrich
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21-12-2016; Nature Publishing Group; Nature Portfolio
• Subjects: 13/89; 14/32; 14/63; 631/378/1686; 631/378/87; Alzheimer's disease; Animals; Axonal Transport - drug effects; Base Sequence; Cells, Cultured; Dynactin Complex - genetics; Dynactin Complex - metabolism; Dyneins - metabolism; Female; Ganglia, Spinal - cytology; Ganglia, Spinal - embryology; Gene Expression - drug effects; Growth factors; Humanities and Social Sciences; Male; multidisciplinary; Nerve Growth Factor - pharmacology; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons - metabolism; Protein synthesis; Proteins; Rats, Sprague-Dawley; RNA Interference; Science; Science (multidisciplinary); Surgeons; New York; United States > US
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms13865

Cytoplasmic dynein mediates retrograde transport in axons, but it is unknown how its transport characteristics are regulated to meet acutely changing demands. We find that stimulus-induced retrograde transport of different cargos requires the local synthesis of different dynein cofactors. Nerve growth factor (NGF)-induced transport of large vesicles requires local synthesis of Lis1, while smaller signalling endosomes require both Lis1 and p150
Glued
. Lis1 synthesis is also triggered by NGF withdrawal and required for the transport of a death signal. Association of Lis1 transcripts with the microtubule plus-end tracking protein APC is required for their translation in response to NGF stimulation but not for their axonal recruitment and translation upon NGF withdrawal. These studies reveal a critical role for local synthesis of dynein cofactors for the transport of specific cargos and identify association with RNA-binding proteins as a mechanism to establish functionally distinct pools of a single transcript species in axons.
The molecular mechanisms underlying retrograde transport in axons are only partially understood. Villarin
et al
. show that in cultured DRG neurons, extracellular trophic cues such as NGF dynamically regulate local protein synthesis of dynein cofactors, thus controlling retrograde trafficking in neurons.