PerspectiveNeuroscience

RNA, Whither Goest Thou?

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Science  08 Jan 1999:
Vol. 283, Issue 5399, pp. 186-187
DOI: 10.1126/science.283.5399.186

The most striking feature of nerve cells [HN1], aside from their spectacular number and the complexity of their interconnections, is the extraordinary functional plasticity of the circuitry. Each of the thousands of synaptic connections [HN2] of a given neuron can be independently modulated, a modulation that requires long-term storage of specific information and thus some form of synaptic memory. We do not know whether such synaptic memory is located in the nucleus, the cell body, or at the synapse itself. If in the nucleus or cell body, a retrograde synapse-to-soma signal would be required, as would a cataloging device in the soma or nucleus to monitor the status of all of the neuron's synapses. No such device has been described to date. If long-term synaptic memory is formed at the synapse, on the other hand, a mechanism must exist to implement at least some aspects of gene expression [HN3] at the synapse itself. How could this be achieved?

Recent work has advanced two answers to this question. The first suggests that stimulation of a given synapse can set a transient tag that would enable that synapse to recruit (“capture”) proteins needed for synaptic modulation. Initial support for this concept has come from experiments showing that stimulation in the presence of protein-synthesis inhibitors could result in late-phase long-term potentiation [HN4] provided that the same population of neurons had previously been stimulated at a different site (1). This is consistent with the notion that the “tagged” second site could recruit proteins that were synthesized after stimulation of the first site. However, the nature of such tags remains unknown, as do the proteins that may be recruited.

The second answer suggests that synaptic memory can be administered by the delivery of selected RNAs to postsynaptic dendritic sites (see figure below). Select dendritic mRNAs, docked at a synaptic target site, can then be translated [HN5] selectively upon demand, for example, as a result of transsynaptic activity or the action of trophic factors (2). In this scheme, some decision-making authority is transferred to the synapse, away from central control in the soma. A prerequisite for such mechanism is the specific transport of a subset of RNAs to dendritic sites. Various RNAs have been identified in dendrites, including mRNAs encoding neurotransmitter receptors (2) [HN6]. Dendritic RNA transport is specific and rapid—several hundred micrometers per hour (3, 4)—and is mediated by cis-acting [HN7] signaling elements within the transported RNAs themselves. Such elements have been mapped to the 3′ untranslated region (3′ UTR) (5, 6) but also to parts of the coding region (6). In the noncoding short RNA polymerase III transcript BC1 RNA (152 nucleotides) [HN8], a dendritic targeting element is contained within a 5′ region of no more than 62 nucleotides (3). No consensus sequence is apparent in such elements, suggesting that targeting competence may be determined by secondary or higher order structure motifs or by more than one motif in modular fashion.

Far from home.

Dendritic and axonal RNA transport in mammalian neurons. Yellow arrows in the dendritic spine (inset) indicate scenarios that could result from transsynaptic activation.

The delivery of specific RNAs to dendrites would allow for localized translational regulation at the synapse. Transsynaptic activity could result in a translational switch, initiating translation of locally docked but translationally inactive mRNAs. This ability to induce the synthesis of selected proteins at the synapse would allow for long-lasting changes in structure and function of that synapse. Support for this notion comes from two recent observations: Neurotrophin-induced synaptic plasticity in the hippocampus [HN9] depends on local translation in CA1 pyramidal cell dendrites (7), and synthesis of a rat homolog of fragile X mental retardation protein is initiated within minutes of stimulation of metabotropic glutamate receptors in synapto-dendritic preparations (8).

Activity-dependent translation in dendrites may also be regulated by the local availability of selected mRNAs, through modulated transport or selective docking to dendritic target sites, or indirectly by activity-dependent regulation of gene expression in the nucleus. Recent work has provided initial support for these notions. Thus, dendritic delivery of BDNF and TrkB mRNAs [HN10] is regulated, in an RNA synthesis-independent manner, by neuronal activity in hippocampal neurons (9). RNA is also translocated into dendrites in response to neurotrophin-3 (10). Other dendritic RNAs, including BC1 RNA (11) and Arc/arg3.1 mRNA [an immediate-early gene transcript that encodes a cytoskeleton-associated protein (12, 13)], are regulated by neuronal activity through modulation of gene expression in the nucleus.

The dendritic localization of Arc mRNA [HN11] is a direct function of synaptic input (14). In dentate granule cells, transsynaptic stimulation results in the selective localization of Arc mRNA only to the dendritic segments in which synapses were activated. Newly synthesized Arc protein accumulates in the same area. These data indicate that as a consequence of synaptic activation, newly synthesized mRNA can be localized to and translated at synapses that have been activated, thus providing a basis for long-lasting forms of activity-dependent synaptic modulation. On the basis of these data, the local synthesis model can be augmented with elements of a modified synaptic tagging hypothesis in which it is RNA, rather than protein, that is being recruited by tagged synapses. Stimulation of a given synapse would thus set a tag at that site that would allow selective delivery or recruitment of dendritic RNAs to that microdomain for local translation.

A further twist has been added to this concept by a recent report that the transcription factor CREB [HN12] can, upon stimulation, be translated from its cognate mRNA in dendrites and after phosphorylation [HN13] be retrogradely transported to the nucleus (15). CREB, a regulator of gene expression in the nucleus, may thus operate as a retrograde signal linking synaptic activation to induction of gene expression. Some questions remain. What is the fate of dendritically synthesized and phosphorylated CREB (pCREB) in the nucleus? Its levels are probably quite low relative to the much larger pool of pCREB originating from other cellular localities, and it is not immediately obvious how the actions of dendritic pCREB in the nucleus could be distinct. Is pCREB of dendritic origin perhaps somehow distinct (pCREBd)? Such pCREBd could then act only on a subset of CRE-containing genes (for example dendrite-relevant genes); experimental support for such a notion, however, has not yet been reported.

Do similar mechanisms exist in axons? In general, RNA transport in mature mammalian axons seems to be the exception rather than the rule and appears to be a particular feature of specialized neurons, such as magnocellular hypothalamic cells and odorant receptor cells in the olfactory epithelium [HN14]. In the latter, odorant receptor mRNAs were identified in axons of olfactory neurons projecting to the olfactory bulb (16, 17), although it remains to be seen whether axonal expression of these receptors plays any functional role, for example, in axonal guidance mechanisms. The mRNA for tyrosine hydroxylase, the rate-limiting enzyme for catecholamine synthesis [HN15], can be detected in the cerebellum and the striatum. Because these regions contain no catecholaminergic cell bodies, only catecholaminergic axons, the mRNA must be present in the axons (18).

In magnocellular neurons [HN16], mRNA encoding the neuropeptide arginine vasopressin (AVP) has been found in axons (see figure below), as have mRNAs for oxytocin (OT) (1921), galanin (22) [HN17], and for BC1 RNA (23, 24). Axonal RNA transport appears to be specific and regulated. Rats challenged by saline in the drinking water up-regulate their AVP mRNA levels 3-fold in the cell body but almost 20-fold in the axon. No relative changes in axons and cell bodies are observed for oxytocin mRNA in the osmotically stressed rats. The rates of increase and recovery for the AVP mRNA differ from the increase and recovery in the same axons for BC1 RNA (24). Oxytocin and AVP mRNAs are also transported to dendrites where they are colocalized with ribosomes [HN18] and small secretory vesicles, suggesting that they are locally translated (6).

Message at the end.

Ultrastructural visualization of AVP mRNA within axons of the hypothalamo-neurohypophyseal system. The immunogold-silver in situ hybridization reaction is in axonal swellings of the neurohypophysis. Scale bars: 1 μm.

CREDIT: A. TREMBLEAU/ELECTRON MICROGRAPH (21).

What is the function of axonal mRNAs? It is unlikely that they are translated; protein synthesis does not seem to occur in mature mammalian axons, except for the axon hillock and the initial unmyelinated segment. Axonal RNAs in mammalian neurons may, however, also serve as a retrograde signal to regulate posttranscriptional activity in the cell body. Such signaling may help to replenish a protein pool (a peptidergic neurotransmitter, for example) quickly and efficiently at times of elevated demands. Consistent with this notion are results from the mutant Brattleboro rat indicating that axonal and dendritic RNAs function quite differently. These data suggest that axonal AVP mRNA transport occurs after the message has been released from the ribosomes, whereas dendritic mRNA localization occurs independently of its association with ribosomes (25) [HN19]. The mRNA may be stably stored in the axon as part of translationally inactive ribonucleoprotein [HN20] (RNP) complexes as in other cells (26). RNP-like particles have indeed been observed in axons of magnocellular neurons, although they could also be ribosomes (27). On the matter of mRNA function in mammalian axons, the jury is still out.

Important issues remain open. What is the significance of dendritic translation of a given mRNA if at the same time the encoded protein can also be targeted from the soma to synaptic sites? The recent data with Arc provide a partial answer in that synaptic activation triggers dendritic localization of the mRNA (14), thus allowing for activity-dependent regulation of local protein repertoires. But the advantages of dendritic translation appear less obvious with the α subunit of CaMKII [HN21], an enzyme that is distributed in neurons including dendrites. Furthermore, what are the signals that predestine a message for translation in the soma or transport to dendrites? Translation of an mRNA does not seem to be required for its dendritic transport (14). Do certain proteins form a complex with the mRNA, or with a pre-initiation complex, to prevent translation? If so, how would such repression then be lifted upon transsynaptic stimulation? Future research will further illuminate the significance of localized RNAs in long-term neuronal plasticity, and thus in higher brain functions [HN22].

Note added in proof. Activity-dependent polyadenylation of dendritic CaMKIIa mRNA may constitute an additional mechanism for regulating translation at the synapse (28).

HyperNotes Related Resources on the World Wide Web

General Hypernotes

The World-Wide Web Virtual Library for Neurosciences is maintained by the Department of Neurology and Neuroscience at Cornell University Medical College.

Neuroscience on the Internet is a searchable and browsable index of neuroscience resources available on the Internet.

A neuroscience glossary is provided for a course on computational neuroscience at the University of Wisconsin.

Cell & Molecular Biology Online, maintained by P. Gammon, collects links to Web resources useful to cell and molecular biologists.

The On-Line Biology Book from Estrella Mountain Community College, Avondale, AZ, includes units on the nervous system and control of gene expression, as well as a glossary.

R. M. Robertson, Department of Biology, Queen's University, Kingston, Canada, provides online lecture notes for a course on integrative neurobiology. The lecture on the Neuron Doctrine includes historical background information.

A module on the Molecular Biology of the Nervous System is part of an online course on neuroanatomy and medical neuroscience offered by the National Academy of Neuropsychology.

A Brief Tour of the Brain, a section of the Mind and Machine Module from Syracuse University, includes a discussion of neurons and their function.

An exploration of the nervous system is offered by E. Chudler of the University of Washington on his Neuroscience for Kids Web site. His home page features an extensive list of links to neuroscience Web resources.

J. Clothier, Department of Psychiatry, University of Arkansas for Medical Sciences, provides reviews of synaptic biology and neurotransmitter systems for a behavioral sciences course.

The MIT Biology Hypertextbook includes discussion of transcription and translation in its Central Dogma section.

In a chapter on the neuroscientific foundation of psychiatry in The American Psychiatric Press Synopsis of Psychiatry, S. Hyman and J. Coyle discuss the anatomy of the neuron, neurotransmitters, and receptors.

Numbered Hypernotes

1. The neuroscience glossary from the University of Wisconsin defines neuron, soma, dendrite, axon, and synapse. An illustrated introduction to the biological neuron is provided in N. Fraser's presentation on neural networks. The Virtual Anatomy Web site, developed by students at Churchill High School in San Antonio, TX, includes an introduction to neurons. A stereoscopic image of a neuron is offered by the Institute of Neuroinformatics, Zurich. Types of neurons are described on the Neuroscience for Kids Web site. “The inner life of neurons” by M. Chicurel and C. DeFranco appeared in the Spring 1995 issue of On the Brain, which is published by the Harvard Mahoney Neuroscience Institute.

2. C. Chudler's Exploring the Nervous System provides an illustrated introduction to the synapse and electron microscope images of synapses. Synaptic transmission is discussed in the tutorial on the biochemistry of nerve transmission offered by the THCME Medical Biochemistry Page, which is maintained by M. King, Terre Haute Center for Medical Education, Indiana State University. ScienceNet includes a discussion of synapses in a series of articles about the brain and nervous system.

3. Gene expression is defined in the On-Line Medical Dictionary from Cancer WEB. Gene expression is defined in the glossary of the Primer on Molecular Genetics available from the Human Genome Project Information Web site. The MIT Biology Hypertextbook includes a section on prokaryotic genetics and gene expression.

4. Long-term potentiation is defined in the On-Line Medical Dictionary. Long-term potentiation is defined in the neuroscience glossary from the University of Wisconsin. On his Page O'Neuroplasticity Web site, E. Hargreaves, Department of Psychology, University of Otago, New Zealand, provides a review of long-term potentiation. G. Wallis discusses neural plasticity in his 1994 thesis for a D.Phil degree in the Department of Experimental Psychology, Oxford University.

5. Messenger RNA, translation, and translational control are defined in the On-Line Medical Dictionary. An introduction to DNA/RNA translation is available from the Life in the Universe Web site.

6. Neurotransmitter is defined in the On-Line Medical Dictionary. A brief discussion of neurotransmitter receptors is available on the THCME Medical Biochemistry Page.

7. The On-Line Medical Dictionary defines cis acting and cis activation.

8. The Mouse Genome Informatics database from the Jackson Laboratory has an entry for the mouse gene BC1.

9. The On-Line Medical Dictionary includes an entry about the hippocampus. E. Hargreaves' Page O' Neuroplasticity includes a presentation on the hippocampus.

10. Brain-derived neurotrophic factor (BNDF) and trk genes are defined in the On-Line Medical Dictionary. The GeneCards Web site from the Bioinformatics Unit and Genome Center of the Weizmann Institute of Science, Israel, has entries for BNDF and NTRK2 [TRKB].

11. The Mouse Genome Informatics database includes an entry for the mouse gene Arc. O. Steward's Web page at the Department of Neuroscience, University of Virginia, provides a brief description of his research and includes an illustration showing the induction of Arc mRNA in the rat hippocampus.

12. The online Dictionary of Cell Biology defines transcription factor and has entries for CREB factor and CREB binding protein. The GeneCards database from the Bioinformatics Unit and Genome Center of the Weizmann Institute of Science, Israel, has an entry for CREB binding protein. The Society for Neuroscience includes an article about CREB and memory in its collection of Brain Briefings.

13. Phosphorylation is defined in the On-Line Medical Dictionary.

14. The Encarta online concise encyclopedia includes an article on the hypothalamus. The Neuroscience Tutorial from the University of Washington School of Medicine includes a section on the hypothalamus and the autonomic nervous system. The location of the hypothalamus is shown on the first illustration in a discussion of the brainstem in the Web tutorial on the brain offered by K. Chan, Department of Anatomical Sciences, University of Queensland, Australia. The Howard Hughes Medical Institute provides a research summary titled “Information coding in the olfactory system” by L. Buck, Department of Neurobiology, Harvard University.

15. Tyrosine hydroxylase and catecholamine are defined in the On-Line Medical Dictionary. A discussion of catecholamines is provided on the THCME Medical Biochemistry Page.

16. The magnocellular pathway is defined in Visionary, an online dictionary for the study of vision. Magnocellular neuron is defined in the On-Line Medical Dictionary. A. B. Brussaard, Faculty of Biology, Vrije Universiteit, Amsterdam, offers an image of magnocellular neurons.

17. Neuropeptide is defined in the On-Line Medical Dictionary. C. Chudler's Exploring the Nervous System provides an illustrated introduction to neurotransmitters and neuroactive peptides. Vasopressin, arginine, oxytocin, and galanin are defined in the On-Line Medical Dictionary. GeneCards are available for AVP [arginine vasopressin], galanin, and oxytocin.

18. Ribosome is defined in the online Dictionary of Cell Biology.

19. E. Mohr and colleagues at the Institut für Zellbiochemie und klinische Neurobiologie, Universität Hamburg, describe their research on axonal and dendritic mRNA transport.

20. Ribonucleoprotein is defined in the BioTech Life Sciences Dictionary from Indiana University. Ribonucleoprotein is defined in the online Dictionary of Cell Biology.

21. The Online Mendelian Inheritance in Man Web site includes an entry for calmodulin-dependent protein kinase type IIA.

22. The online Dictionary of Cell Biology defines neuronal plasticity. L. Cleary and F. O'Leary discuss biochemical and molecular changes to neurons in an article titled “Changes in neuronal structure induced by learning” published in the newsletter of the Neuroscience Research Center of the University of Texas, Houston.

23. H. Tiedge is in the Departments of Pharmacology and Physiology, State University of New York Health Center at Brooklyn.

24. F. E. Bloom is in the Department of Neuropharmacology, Scripps Research Institute, La Jolla, CA.

25. D. Richter is at the Institut für Zellbiochemie und klinische Neurobiologie, Universität Hamburg.

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