Abstract
Programmed cell death 4 (PDCD4) protein is a tumor suppressor that inhibits translation through the mTOR-dependent initiation factor EIF4A, but its functional role and mRNA targets in neurons remain largely unknown. Our work identified that PDCD4 is highly expressed in axons and dendrites of CNS and PNS neurons. Using loss- and gain-of-function experiments in cortical and dorsal root ganglia primary neurons, we demonstrated the capacity of PDCD4 to negatively control axonal growth. To explore PDCD4 transcriptome and translatome targets, we used Ribo-seq and uncovered a list of potential targets with known functions as axon/neurite outgrowth regulators. In addition, we observed that PDCD4 can be locally synthesized in adult axons in vivo, and its levels decrease at the site of peripheral nerve injury and before nerve regeneration. Overall, our findings demonstrate that PDCD4 can act as a new regulator of axonal growth via the selective control of translation, providing a target mechanism for axon regeneration and neuronal plasticity processes in neurons.
Highlights
Previous work in cancer cells demonstrated that both the translation and activity of programmed cell death 4 (PDCD4) can be regulated via the mammalian target of rapamycin (mTOR)-p70S6K pathway (Dorrello et al 2006), prompting us to investigate the potential link between PDCD4 and its upstream regulator p70S6K
Our studies demonstrate that PDCD4 is expressed in different neuronal cell types of the central nervous system (CNS) and peripheral nervous system (PNS) and is distributed in axonal and dendritic compartments, possibly interacting with other components of the mTOR pathway, such as its upstream protein regulator p70S6K (Fig. 1)
The possibility that PDCD4 functions as a translation regulator factor in both cancer and neuronal cells agrees with the observation that many of the key cellular hallmarks of cancer encompass molecular processes that are crucial in nervous system development, such as invasive cell growth, cytoskeleton rearrangements, ECM dynamic interactions and survival (Duman-Scheel 2009; Heine et al 2015)
Summary
The tumor suppressor programmed cell death 4 (PDCD4) protein was first described in cancer studies and has been shown to regulate protein synthesis by inhibition of EIF4A helicase activity (Yang et al 2003; Suzuki et al 2008; Matsuhashi et al 2019) and via interaction with specific RNA motives present in a particular subset of target mRNAs (Loh et al 2009; Wedeken et al 2011; Biyanee et al 2015). The acceptance of local protein translation as a key molecular mechanism in neuronal function has prompted the development of a variety of experimental models and omics approaches to investigate the specific axonal transcriptomes and proteomes (for review, see Farias et al 2020). In this context, the elucidation of the regulatory pathways that can control the selective translation of axonal mRNAs has become an essential step in the understanding of neuronal development, growth and activity (Swanger and Bassell 2011; Jung et al 2012). PDCD4 has been shown to be down-regulated by microRNA-21 (Jiang et al 2017) reinforcing the view of its potential role in neuronal mechanisms
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