- Email: [email protected]
Hidden Figures: A Non-translated RNA Regulates Axonal Neurotrophin Signaling
Neuron
Previews Hidden Figures: A Non-translated RNA Regulates Axonal Neurotrophin Signaling Nicolas Panayotis1 and Mike Fainzilber1,* 1Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2019.04.019
In this issue of Neuron, Crerar et al. (2019) found Tp53inp2 as a highly expressed RNA in sympathetic neuron axons. Strikingly, its long 30 UTR ensures that Tp53inp2 is not translated in axons, and the untranslated RNA affects neuronal growth by interacting with neurotrophin receptors. Neurons traffic a large variety of RNAs to different subcellular compartments, including growth cones, synapses, dendrites, and axons (Rangaraju et al., 2017). Localized translation of different mRNAs has been implicated in growth, regeneration, and functional maintenance of axons (Sahoo et al., 2018). However, neurons also express numerous long non-coding RNAs, some of which affect axonal growth and regeneration (Perry et al., 2018). In this issue of Neuron, the Riccio and Kuruvilla groups identify a highly expressed axonal RNA that defies rigid classification as a coding or a non-coding transcript. Tumor protein p53-inducible nuclear protein 2 (Tp53inp2) is a 3.6 kb transcript containing a short coding sequence and a long 30 UTR of more than 3 kb. Intriguingly, the 30 UTR is the functional domain in axonal Tp53inp2, acting as an untranslated regulator of neurotrophin signaling and neuronal growth (Crerar et al., 2019). Eukaryotic mRNA 50 and 30 UTRs are involved in transcript localization, stability, and translational efficiency. Crerar et al. (2019) took advantage of a compartmentalized culture system to apply nerve growth factor (NGF) to the axonal compartment of embryonic sympathetic neurons and then profiled RNA content of the axons using 30 end-directed RNA sequencing. Tp53inp2, a transcript coding for a small protein that regulates autophagy in skeletal muscle cells (Sala and Zorzano, 2015), was found to be the most abundant mRNA in sympathetic axons. Intriguingly, despite extensive efforts, the endogenous protein was practically undetectable in sympathetic neurons. Crerar et al. (2019) spared no effort to this end, including western blot analyses with multiple antibodies,
monitoring Tp53inp2 translation rates by polysome fractionation, and mass spectrometry analyses from axons and cell bodies of sympathetic neurons. Transfection of the coding sequence in other cell types confirmed that a full-length protein could be translated from the Tp53inp2 transcript, suggesting that Tp53inp2 is translationally repressed in developing sympathetic neurons. As noted above, the Tp53inp2 30 UTR is unusually long (>3,000 nt). Crerar et al. (2019) generated constructs fusing fulllength or progressively shortened versions of the Tp53inp2 30 UTR to a GFP coding sequence and examined the effect of the UTR additions on GFP translation in transfected PC12 cells. The full-length UTR repressed GFP translation, and this repression was alleviated as UTR length was shortened. Moreover, cells with robust endogenous expression of Tp53inp2 protein were found to have transcripts with short 30 UTRs. Taken together with the lack of Tp53inp2 protein in sympathetic neurons, these findings suggest that the long 30 UTR represses translation of Tp53inp2. The Tp53inp2 transcript comprises almost one-third of the RNA content of NGF-stimulated sympathetic axons, prompting Crerar et al. (2019) to ask whether it might influence NGF signaling. The NGF family of neurotrophins signals through the trk family of receptor tyrosine kinases; hence, Crerar et al. (2019) used RNA immunoprecipitation to test for interactions of Tp53inp2 RNA with trk receptors. A pan-trk antibody co-precipitated Tp53inp2 RNA with the NGF receptor TrkA from sympathetic neurons and with the brain-derived neurotrophic factor (BDNF) receptor TrkB from cortical neu-
rons. The RNA binding protein (RBP) HuD was also co-immunoprecipitated with TrkA, suggesting that TrkA interacts with a HuD-Tp53inp2 ribonucleoprotein (RNP) complex in sympathetic neurons. Crerar et al. (2019) then asked what is the functional impact of a non-translated RNA interaction with TrkA on NGF signaling? To address this point, they generated mice with a floxed allele of Tp53inp2 and tested the effects of a conditional Tp53inp2 knockout in isolated axons from superior cervical ganglia (SCG) explants. Axons were severed from the explants and stimulated with NGF, leading to TrkA phosphorylation and trafficking and activation of downstream kinases in the wild type. In contrast, these events were significantly attenuated in Tp53inp2 knockout axons. Moreover, Crerar et al. (2019) found that Tp53inp2-deficient sympathetic neurons stimulated with NGF on distal axons had stunted growth. Remarkably, these axon growth defects were rescued by re-expression of a translation-deficient Tp53inp2 transcript. Thus, Tp53inp2 has functional effects on NGF signaling that are independent of its translational status. Neurotrophin receptor internalization is an essential initial step for formation of the signaling endosomes that convey neurotrophic signals for growth and survival to neuronal cell bodies. Live-cell imaging confirmed that TrkA receptor internalization is decreased in Tp53inp2 conditionally deleted axons. Crerar et al. (2019) then investigated whether the loss of Tp53inp2 would affect survival and growth of SCG neurons in vivo. In situ hybridization experiments confirmed that Tp53inp2 RNA is abundant in the sympathetic neurons at E14.5, an embryonic stage that is
Neuron 102, May 8, 2019 ª 2019 Elsevier Inc. 507
Neuron
Previews
Figure 1. A Non-translated Axonal RNA Influences TrkA Signaling In wild-type sympathetic neurons (top), Tp53inp2 is a highly expressed yet non-translated RNA that interacts with the NGF receptor TrkA. The interaction regulates TrkA internalization and retrograde transport, promoting cell survival and axon growth. In contrast, the conditional deletion of Tp53inp2 in sympathetic neurons (bottom) results in reduced TrkA receptor internalization and attenuation of downstream trophic signals, with consequences for axon growth, cell survival, and target innervation.
highly dependent on NGF for growth and survival. Fluorescent in situ hybridization (FISH) of the Tp53inp2 30 UTR revealed a punctate expression pattern in both axons and cell bodies in wild-type neurons. Conditional deletion of Tp53inp2 abolished the 30 UTR FISH signal in both neuronal compartments. Analyses of the mutant SCGs revealed a normal cell number up until E16.5, followed by significant cell loss at birth (P0.5) and 3 weeks of age (P21), as compared to wild-type littermates. Strikingly, a significant deficit in sympathetic innervation of the heart was observed at E16.6, apparently preceding neuronal loss in SCGs. Since NGF signaling is target derived during development, this suggests that neuronal loss in Tp53inp2 mutants may be a consequence of sympathetic axons failure to reach their targets. Decades of research have established the importance of neurotrophins in sculpting the nervous system through effects on neuronal survival, morphology, and plasticity. The mechanisms governing this signaling system have been analyzed with particular focus on protein-protein
508 Neuron 102, May 8, 2019
interactions and protein complex trafficking within neurons. The new findings by Crerar et al. (2019) represent an important milestone because they introduce RNAs to neurotrophic factor signaling, not as templates or regulators of translation, but rather as active players in initial signaling and trafficking events. Tp53inp2 acts as a non-coding RNA to influence the response of TrkA to NGF binding, and in its absence, receptor endocytosis and downstream trophic effects are impaired (Figure 1). These findings now raise a host of new questions. Does Tp53inp2 regulate BDNF-TrkB or NT3-TrkC signaling in a similar manner to its effects on the NGF-TrkA pathway? Crerar et al. (2019) reported an apparent interaction of Tp53inp2 with TrkB in mouse cortical neurons (albeit based on a pan-trk antibody). If Tp53inp2 indeed interacts with TrkB also in CNS catecholaminergic neurons, it will be interesting to find out whether the conditional Tp53inp2 knockout already reported by Crerar et al. (2019) (using a TH-Cre line) has impaired responses to BDNF signaling in these neurons. Further on this line, are
Tp53inp2 non-coding effects restricted to neurotrophin receptors or is it a general modifier of receptor tyrosine kinase signaling? Are there other such RNAs (Tp53inp2 related or unrelated) with similar functions? How is Tp53inp2 axonal localization regulated? In contrast to the extensive and still expanding lists of axonal mRNAs, there have been limited analyses of axonal roles for most RBPs to date (Sahoo et al., 2018). Many axonal RNAs appear to function in ‘‘RNA regulons,’’ whereby individual RBPs handle multiple mRNAs involved in complementary functions (Lee et al., 2018). Crerar et al. (2019) identified HuD as an RBP that interacts with TrkA in sympathetic axons, although they did not verify whether HuD directly mediates the Tp53inp2-TrkA interaction. Somewhat paradoxically, a recent study reported that HuD acts as a translation enhancer for many of its target mRNAs (Tebaldi et al., 2018). Tebaldi et al. (2018) further reported that the small noncoding RNA Y3 is an abundant HuD interactor and that it sequesters HuD from polysomes, thus counteracting its translation enhancer activity. Thus, Tp53inp2 localization and functionality might be regulated on multiple levels by RBPs and both protein and RNA interactors, with the latter comprising both coding and non-coding RNAs. Could Tp53inp2 also have codingdependent roles in neurons? Although Crerar et al. (2019) showed convincingly that the long 30 UTR maintains translation repression of Tp53inp2 in embryonic sympathetic neurons, the protein is expressed in other cell types and TP53INP2 is a potent activator of autophagy in muscle cells (Sala and Zorzano, 2015). A comparison of the factors controlling Tp53inp2 translation in skeletal muscle versus neurons would be of more than academic interest, since inhibition of TP53INP2 might provide a clinical strategy for the prevention of disease-associated muscle wasting (Sala and Zorzano, 2015). Conversely, release of Tp53inp2 translational repression might enable upregulation of neuronal autophagy upon need. Translation can be upregulated locally in axons by a feedforward loop centered on local translation of the translation regulator mTOR (Terenzio et al., 2018). Another recent study from Riccio
Neuron
Previews and colleagues available as a preprint shows that the 30 UTRs of many transcripts can undergo cleavage by the endonuclease Ago2 in sympathetic neuron axons, generating translatable isoforms with a shorter UTR (Andreassi et al., 2019). The cleavage is mediated by a protein complex containing HuD (Andreassi et al., 2019), which, as noted above, is found in complex with both Tp53inp2 RNA and TrkA protein. Hence, it is intriguing to speculate that coordinated cleavage of the Tp53inp2 30 UTR, together with upregulation of local translation capacity in the axon, might enable switching of non-coding to coding roles of Tp53inp2. The findings of Crerar et al. (2019) highlight a hitherto unknown role at the noncoding level for a protein-coding RNA in axons. This ‘‘hidden role’’ for an abundant RNA became clear only after departing from the prevailing protein-centric viewpoint, a process with parallels in both the history and sociology of science (e.g., Shetterly, 2016). Crerar et al. (2019) have demonstrated a prominent non-cod-
ing role for a protein-coding transcript in neurons, and it will be interesting to find out how widespread such dualities might be in the future.
Rangaraju, V., Tom Dieck, S., and Schuman, E.M. (2017). Local translation in neuronal compartments: how local is local? EMBO Rep. 18, 693–711. Sahoo, P.K., Smith, D.S., Perrone-Bizzozero, N., and Twiss, J.L. (2018). Axonal mRNA transport and translation at a glance. J. Cell Sci. 131, jcs196808, https://doi.org/10.1242/ jcs.196808.
REFERENCES Andreassi, C., Luisier, R., Crerar, H., Franke, S., Luscombe, N.M., Cuda, G., Gaspari, M., and Riccio, A. (2019). 30 UTR cleavage of transcripts localized in axons of sympathetic neurons. bioRxiv. https://doi.org/10.1101/170100. Crerar, H., Scott-Solomon, E., Bodkin-Clarke, C., Andreassi, C., Hazbon, M., Logie, E., CanoJaimez, M., Gaspari, M., Kuruvilla, R., and Riccio, A. (2019). Regulation of NGF signaling by an axonal untranslated mRNA. Neuron 102, this issue, 553–563. Lee, S.J., Oses-Prieto, J.A., Kawaguchi, R., Sahoo, P.K., Kar, A.N., Rozenbaum, M., Oliver, D., Chand, S., Ji, H., Shtutman, M., et al. (2018). hnRNPs interacting with mRNA localization motifs define axonal RNA regulons. Mol. Cell. Proteomics 17, 2091–2106. Perry, R.B., Hezroni, H., Goldrich, M.J., and Ulitsky, I. (2018). Regulation of neuroregeneration by long noncoding RNAs. Mol. Cell 72, 553–567.e5.
Sala, D., and Zorzano, A. (2015). Is TP53INP2 a critical regulator of muscle mass? Curr. Opin. Clin. Nutr. Metab. Care 18, 234–239. Shetterly, M.L. (2016). Hidden Figures: The American Dream and the Untold Story of the Black Women Mathematicians who Helped Win the Space Race, First Edition (William Morrow). Tebaldi, T., Zuccotti, P., Peroni, D., Ko¨hn, M., Gasperini, L., Potrich, V., Bonazza, V., Dudnakova, T., Rossi, A., Sanguinetti, G., et al. (2018). HuD is a neural translation enhancer acting on mTORC1-responsive genes and counteracted by the Y3 small non-coding RNA. Mol. Cell 71, 256–270.e10. Terenzio, M., Koley, S., Samra, N., Rishal, I., Zhao, Q., Sahoo, P.K., Urisman, A., Marvaldi, L., OsesPrieto, J.A., Forester, C., et al. (2018). Locally translated mTOR controls axonal local translation in nerve injury. Science 359, 1416–1421.
Nuclear Pore Complexes Are Key Regulators of Oligodendrocyte Differentiation and Function Marcela Raices1 and Maximiliano A. D’Angelo1,* 1Development, Aging and Regeneration Program and NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2019.04.025
Increasing evidence points to nuclear pore complexes as important regulators of cell fate and tissue homeostasis. A recent report by Liu et al. (2019) in this issue of Neuron uncovers that nucleoporin Seh1 is required for the expression of genes critical for oligodendrocyte differentiation and myelination. Nuclear pore complexes (NPCs) are multiprotein channels that span the nuclear envelope and connect the nucleus to the cytoplasm. In addition to their function controlling nucleo-cytoplasmic molecule exchange, accumulating evidence shows that NPCs have many transport-independent functions. These large multiprotein complexes of >100 MDa in mammals are built by the repeti-
tion of 30 different proteins known as nucleoporins. Historically, NPCs have been viewed as structures of ubiquitous composition with the sole function of allowing the transport of molecules through the nuclear envelope. But a considerable amount of evidence indicates that NPCs are indeed highly dynamic structures that can be modified by changing their composition or stoi-
chiometry to regulate specific cellular processes. Moreover, individual NPC components have been found to have specific cellular functions either at NPCs or away from them. In regard to cell fate, the transmembrane nucleoporin Nup210 was discovered to promote muscle and neuronal differentiation (D’Angelo et al., 2012). Similarly, the scaffold nucleoporin Nup133 was found to play a role in
Neuron 102, May 8, 2019 ª 2019 Elsevier Inc. 509
Previews Hidden Figures: A Non-translated RNA Regulates Axonal Neurotrophin Signaling Nicolas Panayotis1 and Mike Fainzilber1,* 1Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2019.04.019
In this issue of Neuron, Crerar et al. (2019) found Tp53inp2 as a highly expressed RNA in sympathetic neuron axons. Strikingly, its long 30 UTR ensures that Tp53inp2 is not translated in axons, and the untranslated RNA affects neuronal growth by interacting with neurotrophin receptors. Neurons traffic a large variety of RNAs to different subcellular compartments, including growth cones, synapses, dendrites, and axons (Rangaraju et al., 2017). Localized translation of different mRNAs has been implicated in growth, regeneration, and functional maintenance of axons (Sahoo et al., 2018). However, neurons also express numerous long non-coding RNAs, some of which affect axonal growth and regeneration (Perry et al., 2018). In this issue of Neuron, the Riccio and Kuruvilla groups identify a highly expressed axonal RNA that defies rigid classification as a coding or a non-coding transcript. Tumor protein p53-inducible nuclear protein 2 (Tp53inp2) is a 3.6 kb transcript containing a short coding sequence and a long 30 UTR of more than 3 kb. Intriguingly, the 30 UTR is the functional domain in axonal Tp53inp2, acting as an untranslated regulator of neurotrophin signaling and neuronal growth (Crerar et al., 2019). Eukaryotic mRNA 50 and 30 UTRs are involved in transcript localization, stability, and translational efficiency. Crerar et al. (2019) took advantage of a compartmentalized culture system to apply nerve growth factor (NGF) to the axonal compartment of embryonic sympathetic neurons and then profiled RNA content of the axons using 30 end-directed RNA sequencing. Tp53inp2, a transcript coding for a small protein that regulates autophagy in skeletal muscle cells (Sala and Zorzano, 2015), was found to be the most abundant mRNA in sympathetic axons. Intriguingly, despite extensive efforts, the endogenous protein was practically undetectable in sympathetic neurons. Crerar et al. (2019) spared no effort to this end, including western blot analyses with multiple antibodies,
monitoring Tp53inp2 translation rates by polysome fractionation, and mass spectrometry analyses from axons and cell bodies of sympathetic neurons. Transfection of the coding sequence in other cell types confirmed that a full-length protein could be translated from the Tp53inp2 transcript, suggesting that Tp53inp2 is translationally repressed in developing sympathetic neurons. As noted above, the Tp53inp2 30 UTR is unusually long (>3,000 nt). Crerar et al. (2019) generated constructs fusing fulllength or progressively shortened versions of the Tp53inp2 30 UTR to a GFP coding sequence and examined the effect of the UTR additions on GFP translation in transfected PC12 cells. The full-length UTR repressed GFP translation, and this repression was alleviated as UTR length was shortened. Moreover, cells with robust endogenous expression of Tp53inp2 protein were found to have transcripts with short 30 UTRs. Taken together with the lack of Tp53inp2 protein in sympathetic neurons, these findings suggest that the long 30 UTR represses translation of Tp53inp2. The Tp53inp2 transcript comprises almost one-third of the RNA content of NGF-stimulated sympathetic axons, prompting Crerar et al. (2019) to ask whether it might influence NGF signaling. The NGF family of neurotrophins signals through the trk family of receptor tyrosine kinases; hence, Crerar et al. (2019) used RNA immunoprecipitation to test for interactions of Tp53inp2 RNA with trk receptors. A pan-trk antibody co-precipitated Tp53inp2 RNA with the NGF receptor TrkA from sympathetic neurons and with the brain-derived neurotrophic factor (BDNF) receptor TrkB from cortical neu-
rons. The RNA binding protein (RBP) HuD was also co-immunoprecipitated with TrkA, suggesting that TrkA interacts with a HuD-Tp53inp2 ribonucleoprotein (RNP) complex in sympathetic neurons. Crerar et al. (2019) then asked what is the functional impact of a non-translated RNA interaction with TrkA on NGF signaling? To address this point, they generated mice with a floxed allele of Tp53inp2 and tested the effects of a conditional Tp53inp2 knockout in isolated axons from superior cervical ganglia (SCG) explants. Axons were severed from the explants and stimulated with NGF, leading to TrkA phosphorylation and trafficking and activation of downstream kinases in the wild type. In contrast, these events were significantly attenuated in Tp53inp2 knockout axons. Moreover, Crerar et al. (2019) found that Tp53inp2-deficient sympathetic neurons stimulated with NGF on distal axons had stunted growth. Remarkably, these axon growth defects were rescued by re-expression of a translation-deficient Tp53inp2 transcript. Thus, Tp53inp2 has functional effects on NGF signaling that are independent of its translational status. Neurotrophin receptor internalization is an essential initial step for formation of the signaling endosomes that convey neurotrophic signals for growth and survival to neuronal cell bodies. Live-cell imaging confirmed that TrkA receptor internalization is decreased in Tp53inp2 conditionally deleted axons. Crerar et al. (2019) then investigated whether the loss of Tp53inp2 would affect survival and growth of SCG neurons in vivo. In situ hybridization experiments confirmed that Tp53inp2 RNA is abundant in the sympathetic neurons at E14.5, an embryonic stage that is
Neuron 102, May 8, 2019 ª 2019 Elsevier Inc. 507
Neuron
Previews
Figure 1. A Non-translated Axonal RNA Influences TrkA Signaling In wild-type sympathetic neurons (top), Tp53inp2 is a highly expressed yet non-translated RNA that interacts with the NGF receptor TrkA. The interaction regulates TrkA internalization and retrograde transport, promoting cell survival and axon growth. In contrast, the conditional deletion of Tp53inp2 in sympathetic neurons (bottom) results in reduced TrkA receptor internalization and attenuation of downstream trophic signals, with consequences for axon growth, cell survival, and target innervation.
highly dependent on NGF for growth and survival. Fluorescent in situ hybridization (FISH) of the Tp53inp2 30 UTR revealed a punctate expression pattern in both axons and cell bodies in wild-type neurons. Conditional deletion of Tp53inp2 abolished the 30 UTR FISH signal in both neuronal compartments. Analyses of the mutant SCGs revealed a normal cell number up until E16.5, followed by significant cell loss at birth (P0.5) and 3 weeks of age (P21), as compared to wild-type littermates. Strikingly, a significant deficit in sympathetic innervation of the heart was observed at E16.6, apparently preceding neuronal loss in SCGs. Since NGF signaling is target derived during development, this suggests that neuronal loss in Tp53inp2 mutants may be a consequence of sympathetic axons failure to reach their targets. Decades of research have established the importance of neurotrophins in sculpting the nervous system through effects on neuronal survival, morphology, and plasticity. The mechanisms governing this signaling system have been analyzed with particular focus on protein-protein
508 Neuron 102, May 8, 2019
interactions and protein complex trafficking within neurons. The new findings by Crerar et al. (2019) represent an important milestone because they introduce RNAs to neurotrophic factor signaling, not as templates or regulators of translation, but rather as active players in initial signaling and trafficking events. Tp53inp2 acts as a non-coding RNA to influence the response of TrkA to NGF binding, and in its absence, receptor endocytosis and downstream trophic effects are impaired (Figure 1). These findings now raise a host of new questions. Does Tp53inp2 regulate BDNF-TrkB or NT3-TrkC signaling in a similar manner to its effects on the NGF-TrkA pathway? Crerar et al. (2019) reported an apparent interaction of Tp53inp2 with TrkB in mouse cortical neurons (albeit based on a pan-trk antibody). If Tp53inp2 indeed interacts with TrkB also in CNS catecholaminergic neurons, it will be interesting to find out whether the conditional Tp53inp2 knockout already reported by Crerar et al. (2019) (using a TH-Cre line) has impaired responses to BDNF signaling in these neurons. Further on this line, are
Tp53inp2 non-coding effects restricted to neurotrophin receptors or is it a general modifier of receptor tyrosine kinase signaling? Are there other such RNAs (Tp53inp2 related or unrelated) with similar functions? How is Tp53inp2 axonal localization regulated? In contrast to the extensive and still expanding lists of axonal mRNAs, there have been limited analyses of axonal roles for most RBPs to date (Sahoo et al., 2018). Many axonal RNAs appear to function in ‘‘RNA regulons,’’ whereby individual RBPs handle multiple mRNAs involved in complementary functions (Lee et al., 2018). Crerar et al. (2019) identified HuD as an RBP that interacts with TrkA in sympathetic axons, although they did not verify whether HuD directly mediates the Tp53inp2-TrkA interaction. Somewhat paradoxically, a recent study reported that HuD acts as a translation enhancer for many of its target mRNAs (Tebaldi et al., 2018). Tebaldi et al. (2018) further reported that the small noncoding RNA Y3 is an abundant HuD interactor and that it sequesters HuD from polysomes, thus counteracting its translation enhancer activity. Thus, Tp53inp2 localization and functionality might be regulated on multiple levels by RBPs and both protein and RNA interactors, with the latter comprising both coding and non-coding RNAs. Could Tp53inp2 also have codingdependent roles in neurons? Although Crerar et al. (2019) showed convincingly that the long 30 UTR maintains translation repression of Tp53inp2 in embryonic sympathetic neurons, the protein is expressed in other cell types and TP53INP2 is a potent activator of autophagy in muscle cells (Sala and Zorzano, 2015). A comparison of the factors controlling Tp53inp2 translation in skeletal muscle versus neurons would be of more than academic interest, since inhibition of TP53INP2 might provide a clinical strategy for the prevention of disease-associated muscle wasting (Sala and Zorzano, 2015). Conversely, release of Tp53inp2 translational repression might enable upregulation of neuronal autophagy upon need. Translation can be upregulated locally in axons by a feedforward loop centered on local translation of the translation regulator mTOR (Terenzio et al., 2018). Another recent study from Riccio
Neuron
Previews and colleagues available as a preprint shows that the 30 UTRs of many transcripts can undergo cleavage by the endonuclease Ago2 in sympathetic neuron axons, generating translatable isoforms with a shorter UTR (Andreassi et al., 2019). The cleavage is mediated by a protein complex containing HuD (Andreassi et al., 2019), which, as noted above, is found in complex with both Tp53inp2 RNA and TrkA protein. Hence, it is intriguing to speculate that coordinated cleavage of the Tp53inp2 30 UTR, together with upregulation of local translation capacity in the axon, might enable switching of non-coding to coding roles of Tp53inp2. The findings of Crerar et al. (2019) highlight a hitherto unknown role at the noncoding level for a protein-coding RNA in axons. This ‘‘hidden role’’ for an abundant RNA became clear only after departing from the prevailing protein-centric viewpoint, a process with parallels in both the history and sociology of science (e.g., Shetterly, 2016). Crerar et al. (2019) have demonstrated a prominent non-cod-
ing role for a protein-coding transcript in neurons, and it will be interesting to find out how widespread such dualities might be in the future.
Rangaraju, V., Tom Dieck, S., and Schuman, E.M. (2017). Local translation in neuronal compartments: how local is local? EMBO Rep. 18, 693–711. Sahoo, P.K., Smith, D.S., Perrone-Bizzozero, N., and Twiss, J.L. (2018). Axonal mRNA transport and translation at a glance. J. Cell Sci. 131, jcs196808, https://doi.org/10.1242/ jcs.196808.
REFERENCES Andreassi, C., Luisier, R., Crerar, H., Franke, S., Luscombe, N.M., Cuda, G., Gaspari, M., and Riccio, A. (2019). 30 UTR cleavage of transcripts localized in axons of sympathetic neurons. bioRxiv. https://doi.org/10.1101/170100. Crerar, H., Scott-Solomon, E., Bodkin-Clarke, C., Andreassi, C., Hazbon, M., Logie, E., CanoJaimez, M., Gaspari, M., Kuruvilla, R., and Riccio, A. (2019). Regulation of NGF signaling by an axonal untranslated mRNA. Neuron 102, this issue, 553–563. Lee, S.J., Oses-Prieto, J.A., Kawaguchi, R., Sahoo, P.K., Kar, A.N., Rozenbaum, M., Oliver, D., Chand, S., Ji, H., Shtutman, M., et al. (2018). hnRNPs interacting with mRNA localization motifs define axonal RNA regulons. Mol. Cell. Proteomics 17, 2091–2106. Perry, R.B., Hezroni, H., Goldrich, M.J., and Ulitsky, I. (2018). Regulation of neuroregeneration by long noncoding RNAs. Mol. Cell 72, 553–567.e5.
Sala, D., and Zorzano, A. (2015). Is TP53INP2 a critical regulator of muscle mass? Curr. Opin. Clin. Nutr. Metab. Care 18, 234–239. Shetterly, M.L. (2016). Hidden Figures: The American Dream and the Untold Story of the Black Women Mathematicians who Helped Win the Space Race, First Edition (William Morrow). Tebaldi, T., Zuccotti, P., Peroni, D., Ko¨hn, M., Gasperini, L., Potrich, V., Bonazza, V., Dudnakova, T., Rossi, A., Sanguinetti, G., et al. (2018). HuD is a neural translation enhancer acting on mTORC1-responsive genes and counteracted by the Y3 small non-coding RNA. Mol. Cell 71, 256–270.e10. Terenzio, M., Koley, S., Samra, N., Rishal, I., Zhao, Q., Sahoo, P.K., Urisman, A., Marvaldi, L., OsesPrieto, J.A., Forester, C., et al. (2018). Locally translated mTOR controls axonal local translation in nerve injury. Science 359, 1416–1421.
Nuclear Pore Complexes Are Key Regulators of Oligodendrocyte Differentiation and Function Marcela Raices1 and Maximiliano A. D’Angelo1,* 1Development, Aging and Regeneration Program and NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2019.04.025
Increasing evidence points to nuclear pore complexes as important regulators of cell fate and tissue homeostasis. A recent report by Liu et al. (2019) in this issue of Neuron uncovers that nucleoporin Seh1 is required for the expression of genes critical for oligodendrocyte differentiation and myelination. Nuclear pore complexes (NPCs) are multiprotein channels that span the nuclear envelope and connect the nucleus to the cytoplasm. In addition to their function controlling nucleo-cytoplasmic molecule exchange, accumulating evidence shows that NPCs have many transport-independent functions. These large multiprotein complexes of >100 MDa in mammals are built by the repeti-
tion of 30 different proteins known as nucleoporins. Historically, NPCs have been viewed as structures of ubiquitous composition with the sole function of allowing the transport of molecules through the nuclear envelope. But a considerable amount of evidence indicates that NPCs are indeed highly dynamic structures that can be modified by changing their composition or stoi-
chiometry to regulate specific cellular processes. Moreover, individual NPC components have been found to have specific cellular functions either at NPCs or away from them. In regard to cell fate, the transmembrane nucleoporin Nup210 was discovered to promote muscle and neuronal differentiation (D’Angelo et al., 2012). Similarly, the scaffold nucleoporin Nup133 was found to play a role in
Neuron 102, May 8, 2019 ª 2019 Elsevier Inc. 509