Neurotrophins: Neurotrophic modulation of neurite growth

Neurotrophins: Neurotrophic modulation of neurite growth

bb10e07.qxd 03/13/2000 R198 01:49 Page R198 Dispatch Neurotrophins: Neurotrophic modulation of neurite growth Alun M. Davies As well as regulat...

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Neurotrophins: Neurotrophic modulation of neurite growth Alun M. Davies

As well as regulating neuronal survival, neurotrophins control the growth of axons and dendrites. New light has been shed on the mechanism of this latter control process by the discovery that the common neurotrophin receptor p75NTR interacts in a ligand-dependent manner with RhoA, a known regulator of actin assembly. Address: School of Biology, Bute Medical Buildings, University of St. Andrews, St. Andrews, Fife KY16 9TS, UK. E-mail: [email protected] Current Biology 2000, 10:R198–R200 0960-9822/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved.

The neurotrophins are a family of structurally related, secreted proteins that have a profound influence on the development and functioning of the nervous system [1]. Four members of this family have been identified in birds and mammals: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4). Experimental manipulation of the availability of neurotrophins within the developing nervous system has shown that these proteins play a key role in regulating the size of certain populations of neurons by influencing cell survival. Some populations of neurons are dependent on a supply of one or more neurotrophins for survival, whereas in a few well-substantiated cases, NGF promotes cell death. Numerous studies in recent years have revealed that neurotrophins also influence synaptic function. But one of the most striking actions of neurotrophins — the feature for which NGF was originally named — is the promotion of neurite growth. The most extensive data on this have come from studying the effects of NGF on the morphology of NGF-dependent neurons of the developing and adult peripheral nervous system. Numerous studies of sensory and sympathetic neurons have shown that the local availability of NGF influences the extent of terminal axonal branching and dendritic complexity in vivo and enhances neurite extension in vitro [2,3]. The recent demonstration of an interaction between the common neurotrophin receptor p75NTR and RhoA, and hence of a link between neurotrophins and the actin cytoskeleton [4], is an important advance in our understanding of the molecular basis of the neurite-growth-promoting effects of NGF and other neurotrophins. To understand the significance of this latest advance, it is necessary to consider the features and functions of the neurotrophin receptors. Two kinds of transmembrane

glycoprotein are receptors for neurotrophins: members of the Trk family of receptor tyrosine kinases, which are receptors for different specific neurotrophins, and p75NTR, which is a common receptor for all neurotrophins [5]. Accordingly, the pattern of expression of these receptors in neurons differs: whereas each Trk receptor is restricted to a particular set of neurons, p75NTR is usually co-expressed with Trks in many different kinds of neurons and is additionally expressed by several other cell types. Trk receptor tyrosine kinases undergo rapid transphosphorylation following ligand binding, leading to a cascade of protein phosphorylations in the cell. Expression studies in cell lines have shown that TrkA is a receptor for NGF, TrkB is a receptor for BDNF or NT-4, and TrkC is a receptor for NT-3. NT-3 can also bind and signal, albeit less efficiently, via TrkA and TrkB [5]. The finding that the distinctive neuronal deficiencies in mice with null mutations in the trkA, trkB and trkC genes are similar to those observed in mice with null mutations in the NGF, BDNF and NT-3 genes, respectively, suggests that the Trks mediate the survival-promoting actions of neurotrophins on developing neurons. The functions of p75NTR are more diverse and complex than those of the Trks. In vitro studies of neurons obtained from p75NTR null mice, and studies using mutated neurotrophins that have altered binding affinity for p75NTR, have shown that p75NTR selectively modulates the Trk-mediated survival response of neurons to neurotrophins [6]. For example, p75NTR enhances the sensitivity of TrkA-expressing neurons to the survivalpromoting effects of NGF, whilst decreasing their sensitivity to NT-3, and plays a role in ligand discrimination by TrkB. Direct interaction between p75NTR and Trk receptors, together with changes in ligand affinity and Trk signalling, account at least in part for these effects of p75NTR [5,7]; there is, however, some evidence that p75NTR-mediated activation of the transcription factor NF-κB plays a role in enhancing the survival response of developing sensory neurons to NGF [8]. As well as selectively modulating the trophic actions of neurotrophins, p75NTR promotes the death of some neurons and other cell types. Ligand-independent, p75NTR-mediated cell death has been described in some cell lines and in postnatal neurons from the dorsal root ganglion in vitro. Neurotrophin-induced, p75NTR-mediated cell death has been described in proprioceptive and sympathetic neurons and oligodendrocytes in vitro, and has also been observed in the developing retina, spinal cord,

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sympathetic ganglia and cholinergic basal forebrain nuclei in vivo [9]. Neurotrophin receptor interacting factor (NRIF), a recently identified protein that interacts with the intracellular domain of p75NTR, appears to be involved in transducing the cell-death signal, because the reduced cell death observed in the developing retina of nrif–/– mice is quantitatively indistinguishable from that seen in p75NTR–/– and ngf–/– mice [10]. A recent search [4] for additional factors that interact with p75NTR has not only led to direct evidence that p75NTR has a role in modulating axonal growth, but has also provided a likely molecular explanation for this effect. Using an expression library representing E5 chicken retinal cells in a yeast two-hybrid screen, Yamashita et al. [4] identified RhoA as a protein that interacts with the intracellular domain of p75NTR. RhoA is one of three Rho isoforms, members of the Ras superfamily of GTP-binding proteins. Rho proteins have been shown to control the organisation of the actin cytoskeleton in many cell types. Like other members of the Ras superfamily, they cycle between active, GTP-bound and inactive, GDP-bound states. Rho activation in fibroblasts, for example, causes bundling of actin filaments into stress fibres and the clustering of integrins and associated proteins into focal adhesion complexes [11]. In addition to confirming the interaction between p75NTR and RhoA by coimmunoprecipitation, Yamashita et al. [4] used in vivo nucleotide-labelling experiments and affinity precipitation of GTP–Rho in cultured cells to show that p75NTR constitutively activates RhoA, and that NGF, BDNF and NT-3 induce rapid loss of Rho activation. To determine if the ligand-dependent interaction of p75NTR with RhoA modulates neurite growth, Yamashita et al. [4] studied chicken ciliary ganglion neurons that express p75 but not Trk receptors. NGF, BDNF and NT-3 each enhanced the growth of neurites from these neurons in culture, as did the introduction into these neurons of the Rho-inactivating enzyme C3 transferase. Furthermore, the finding that introduction of a constitutively-active mutant form of Rho protein into ciliary neurons inhibited the action of NGF on neurite growth is consistent with the idea that Rho inactivation lies downstream of p75NTR in this response to NGF [4]. Support for the developmental relevance of these observations came from analysing nerve growth in mouse embryos that carry a targeted deletion of the third exon of the p75NTR gene but still express a truncated form of p75NTR that has the transmembrane domain and the cytoplasmic domain that activates RhoA. The finding that during the early stages of axonal outgrowth, the intercostal nerves and forelimb motor axons of mice that are homozygous for the truncation mutation of the p75NTR gene are shorter than those of heterozygous and wild-type mice suggests

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that p75NTR plays a role in enhancing axonal grow in vivo during at least this early stage of development [4]. Several earlier observations have also implicated p75NTR in neurite growth and cell migration, though they provided little indication of the underlying mechanism. For example, embryonic chicken dorsal root ganglion neurons cultured at the stage when their axons are starting to grow to their targets were found to have a more immature appearance, with shorter neurites, in medium containing antisense oligonucleotides that decrease p75NTR expression compared to a control [12]. This delay in neurite growth appears to depend on the production of BDNF by early dorsal root ganglion neurons, as antisense BDNF oligonucleotides have a similar effect to antisense p75NTR oligonucleotides [12]. The absence of sympathetic innervation of the pineal gland and a subset of sweat glands in p75NTR–/– mice [13], despite no apparent loss of sympathetic neurons in these mice, suggests that p75NTR is required for some sympathetic axons to innervate their targets. The finding that Schwann cells, which express p75NTR but not TrkA, migrate more rapidly on cryostat sections of sciatic nerve when treated with NGF, and the observation that this effect of NGF is abolished by anti-p75NTR antibodies, suggest that NGF enhances the migration of these cells by binding to p75NTR [14]. Although the precise region of the p75NTR intracellular domain that interacts with RhoA has not yet been ascertained, there is a short sequence in the intracellular domain that is similar to mastoparan, a 14-residue peptide of wasp venom which is known to be capable of activating Rho [15]. Interestingly, a peptide identical to this sequence in the p75NTR intracellular domain enhances neurite growth in PC12 cells and sensory neurons cultured in the presence of sub-saturating concentrations of NGF, without having any effect on cell survival [16]. In addition to regulating neurite growth by modulating Rho activation, a recent study suggests that ligand binding to p75NTR may also enhance neurite outgrowth by the production of ceramide [17]. NGF was found to accelerate neurite formation and outgrowth from cultured hippocampal pyramidal neurons at a stage when they express p75NTR but not TrkA. NGF treatment stimulated the production of ceramide, and blocking ceramide production with the sphingomyelinase inhibitor scyphostatin inhibited the neuritogenic effects of NGF [17]. In addition to promoting or modulating neurite growth by binding to p75NTR, it is important to point out that neurotrophins also promote neurite growth by binding to Trk receptors and activating downstream signalling pathways [5]. The new study by Yamashita et al. [4] has brought to the forefront a new and exciting chapter in the biology of the p75 receptor. In future work it will be important to ascertain the relative importance of p75NTR and Trk receptors

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in modulating different phases of axonal growth, such as the initial growth and guidance of axons to their targets, terminal arborisation and remodelling of axonal connections within their target field and in regeneration following injury. Also, it will be interesting to ascertain to what extent the regulation of axonal growth by p75NTR differs in different kinds of neurons. For example, recent studies of postnatal sympathetic neurons suggest that BDNF acting via p75NTR inhibits neurite extension [18]. At the molecular level, it will be important to understand the chain of events initiated by p75NTR and Trk signalling that culminate in changes in the cytoskeleton and axonal growth. References 1. Lewin GR, Barde YA: The physiology of neurotrophins. Annu Rev Neurosci 1996, 19:289-317. 2. Edwards RH, Rutter WJ, Hanahan D: Directed expression of NGF to pancreatic beta cells in transgenic mice leads to selective hyperinnervation of the islets. Cell 1989, 58:161-170. 3. Purves D, Snider WD, Voyvodic JT: Trophic regulation of nerve cell morphology and innervation in the autonomic nervous system. Nature 1988, 336:123-128. 4. Yamashita T, Tucker KL, Barde YA: Neurotrophin binding to the p75 receptor modulates Rho activity and axonal outgrowth. Neuron 1999, 24:585-593. 5. Kaplan DR, Miller FD: Signal transduction by the neurotrophin receptors. Curr Opin Cell Biol 1997, 9:213-221. 6. Davies AM: The yin and yang of nerve growth factor. Curr Biol 1997, 7:38-40. 7. Bibel M, Hoppe E, Barde YA: Biochemical and functional interactions between the neurotropin receptors Trk and p75NTR. EMBO J 1999, 18:616-622. 8. Hamanoue M, Middleton G, Wyatt S, Jaffrey E, Hay RT, Davies AM: κB activation enhances the survival response p75-mediated NF-κ of developing sensory neurons to nerve growth factor. Mol Cell Neurosci 1999, 14:28-40. 9. Frade JM, Barde YA: Nerve growth factor: two receptors, multiple functions. Bioessays 1998, 20:137-145. 10. Casademunt E, Carter BD, Benzel I, Frade JM, Dechant G, Barde YA: The zinc finger protein NRIF interacts with the neurotrophin receptor p75(NTR) and participates in programmed cell death. EMBO J 1999, 18:6050-6061. 11. Mackay DJ, Hall A: Rho GTPases. J Biol Chem 1998, 273:20685-20688. 12. Wright EM, Vogel KS, Davies AM: Neurotrophic factors promote the maturation of developing sensory neurons before they become dependent on these factors for survival. Neuron 1992, 9:139-150. 13. Lee KF, Bachman K, Landis S, Jaenisch R: Dependence on p75 for innervation of some sympathetic targets. Science 1994, 263:1447-1449. 14. Anton ES, Weskamp G, Reichardt LF, Matthew WD: Nerve growth factor and its low-affinity receptor promote Schwann cell migration. Proc Natl Acad Sci USA 1994, 91:2795-2799. 15. Koch G, Haberman B, Mohr C, Just I, Aktories K: Interaction of mastoparan with the low molecular mass GTP-binding proteins rho/rac. FEBS Lett 1991, 291:336-340. 16. Dostaler SM, Ross GM, Myers SM, Weaver DF, Ananthanarayanan V, Riopelle RJ: Characterization of a distinctive motif of the low molecular weight neurotrophin receptor that modulates NGF-mediated neurite growth. Eur J Neurosci 1996, 8:870-879. 17. Brann AB, Scott R, Neuberger Y, Abulafia D, Boldin S, Fainzilber M, Futerman AH: Ceramide signaling downstream of the p75 neurotrophin receptor mediates the effects of nerve growth factor on outgrowth of cultured hippocampal neurons. J Neurosci 1999, 19:8199-8206. 18. Kohn J, Aloyz RS, Toma JG, Haak-Frendscho M, Miller FD: Functionally antagonistic interactions between the TrkA and p75 neurotrophin receptors regulate sympathetic neuron growth and target innervation. J Neurosci 1999, 19:5393-5408.

If you found this dispatch interesting, you might also want to read the February 1999 issue of

Current Opinion in Neurobiology which included the following reviews, edited by David J Anderson and Lynn T Landmesser, on Development: Control of neurogenesis — lessons from frogs, fish and flies Ajay B Chitnis Specification of dopaminergic and serotonergic neurons in the vertebrate CNS Mary Hynes and Arnon Rosenthal The roles of intrinsic and extrinsic cues and bHLH genes in the determination of retinal cell fates Constance L Cepko Transcriptional control of neurotransmitter phenotype Christo Goridis and Jean-François Brunet Control of muscle fibre and motoneuron diversification Simon M Hughes and Patricia C Salinas Eph receptors and ephrins in neural development Dennis DM O’Leary and David G Wilkinson Development of the vertebrate main olfactory system David M Lin and John Ngai Formation of lamina-specific synaptic connections Joshua R Sanes and Masahito Yamagata Neuronal activity during development: permissive or instructive? Michael C Crair The origin of spontaneous activity in developing networks of the vertebrate nervous system Michael J O’Donovan Neurotrophin regulation of synaptic transmission Erin M Schuman Gene regulation by patterned electrical activity during neural and skeletal muscle development Andres Buonanno and R Douglas Fields Sensitive periods and circuits for learned birdsong Richard Mooney Maternal care and the development of stress responses Darlene D Francis and Michael J Meaney Stem cells in the adult mammalian central nervous system Sally Temple and Arturo Alvarez-Buylla The full text of Current Opinion in Neurobiology is in the BioMedNet library at http://BioMedNet.com/cbiology/jnrb