Abstract
Neurotrophins provide trophic and tropic support for different neuronal subpopulations in the developing and adult nervous systems. Expression of the neurotrophins and their receptors can be altered in several different disease or injury states that impact upon the functions in the central and peripheral nervous systems. The intracellular signals used by the neurotrophins are triggered by ligand binding to the cell surface Trk and p75NTR receptors. In general, signals emanating from Trk receptors support survival, growth and synaptic strengthening, while those emanating from p75NTR induce apoptosis, attenuate growth and weaken synaptic signaling. Mature neurotrophins are the preferred ligand for Trk proteins while p75NTR binds preferentially to the proneurotrophins and serves as a signaling component of the receptor complex for growth inhibitory molecules of central nervous system myelin [ie, myelin‐associated glycoprotein (MAG), oligodendrocyte‐myelin glycoprotein (OMgP) and Nogo]. The functional antagonism between Trk and p75NTR signaling may significantly impact the pathogenesis of human neurodevelopmental and neurodegenerative diseases and further complicate therapeutic uses of exogenous neurotrophins. The potential for each is discussed in this review.
INTRODUCTION
Neurotrophins are a group of structurally related polypeptide growth factors that contribute to the development, maintenance and function of the peripheral and central nervous systems (PNS and CNS, respectively). These trophic factors have unique activities on target neurons and, more recently recognized, on other cell types in the nervous system and beyond that warrant consideration in the pathophysiology of diseases and injury responses in the human nervous system. The accompanying reviews in this mini‐symposium focus on distinct diseases or disease processes in which actions of the neurotrophins have been clearly implicated (16, 105, 155, 159). In most settings, a decrease or a presumed decrease in effective neurotrophin levels is detrimental. However, increases in neurotrophins can also alter cellular function in harmful ways. This bears particular consideration for inflammatory states, neoplasia and when considering therapeutic potentials for neurotrophins. There have been several recently published general and specialized reviews focusing on neurotrophins’ biological effects and signaling mechanisms (38, 153, 199, 201). Here, we will present mechanisms of actions of mammalian neurotrophins that raise unique considerations for neurotrophin pathophysiology with regard to human CNS and PNS diseases of pathological interest.
The biological activity of nerve growth factor (NGF), the first known neurotrophin, was initially identified in the 1950s from seminal transplantation experiments performed by Victor Hamburger and Rita Levi‐Montalcini (115). These and other experiments led to the “neurotrophic hypothesis” that developing neurons compete for limited quantities of neurotrophic factors that are secreted by their target tissues. The target‐derived trophic activity that the chick dorsal root ganglion (DRG) neurons competed for was coined “nerve growth factor” (41, 116). Isolation of NGF provided the necessary reagents and knowledge to fuel over three decades of fruitful research into the range of NGF’s biological activities and its mechanism of action (114). Shortly after the Nobel Prize was awarded to Levi‐Montalcini and Cohen in 1986 for the identification of NGF (and epidermal growth factor), it was recognized that NGF is only a single member of a family of neurotrophins. Indeed, when Liebrock et al isolated brain‐derived neurotrophic factor (BDNF), structural homologies between BDNF and NGF pointed to a family of related neurotrophic proteins (112).
With the advent of polymerase chain reaction (PCR), other members of the neurotrophin family were rapidly discovered, including neurotrophin‐3 (NT‐3), neurotrophin‐4 (NT‐4) and neurotrophin‐5 (NT‐5) (13, 49, 72, 79, 87, 88, 127, 156). NT‐4 and NT‐5 represent the Xenopus and mammalian orthologs of a single gene product and will be referred to as NT‐4/5 in the remainder of this text. Two additional neurotrophins have been identified in fish, neurotrophin‐6 (NT‐6) and neurotrophin‐7 (NT‐7) (139). The neurotrophins bind to members of a family of tyrosine kinase receptors, the tropomyosin‐related kinases (Trks) TrkA, TrkB and TrkC (81). Additionally, all members of the neurotrophin family bind to a second receptor protein, p75NTR, which was first identified as the NGF receptor (37).
SYNTHESIS AND ACTIVITIES OF NEUROTROPHINS
Neurotrophins are synthesized by a number of different cell types in the CNS and PNS. In general, the individual neurotrophins act upon different neuronal populations or subpopulations, but there can be overlaps in ligand responsiveness. Injury and other stimuli can also alter the repertoire of Trk receptor expression, changing a neuron’s ligand responsiveness. In the CNS, BDNF expression is overall more widespread than that of NGF, NT‐3 or NT‐4/5. Injury and neuronal activity can similarly alter the production of neurotrophins by target tissues and glial cells in the CNS and PNS (62, 131). The four mammalian neurotrophin genes encode prepropeptides, which are secreted as mature proteins. It has now become clear that the propeptides, at least NGF and BDNF, can be secreted and in some cases are processed extracellularly into mature proteins by activities of plasmin, metalloproteases or other as yet unidentified proteases (119). The mature neurotrophins are active as noncovalently linked homodimers. NGF, BDNF, NT‐3 and NT‐4/5 share approximately 50% identity (117). BDNF is secreted through both constitutive and regulated pathways (eg, activity‐dependent). While it has been suggested that the other neurotrophins only show constitutive secretion, activity‐dependent release of NGF and NT‐3 has been demonstrated in some systems (19, 29, 189).
The neurotrophins are essential for proper development of the embryonic nervous system through their ability to promote survival and stimulate neurite outgrowth from CNS and PNS neurons (117). After development, neurotrophins play critical roles in maintaining neuronal morphologies and functions as well as providing trophic and tropic activities in the neuronal responses to injury (15, 168). Although most experimental efforts have focused on activities of the mature neurotrophins, recent observations indicate that proneurotrophins are biologically active and actually counter the growth‐promoting and survival effects of the mature proteins (76).
NGF. In the PNS, NGF promotes survival and maturation of sympathetic and sensory neurons (117). Mice with the NGF gene “knocked out” (NGF−/−) exhibit severe loss of sympathetic and sensory neurons in the PNS (43). The small nociceptive neurons in the DRG, which mediate pain and temperature sensation, do not survive in animals treated with neutralizing NGF antibodies or in the NGF−/− mice (167). Clinically, trophic activity of NGF in the sensory nervous system, particularly the small nociceptive fibers, has been suggested to contribute to diabetic neuropathy (178), and mutations of the NGF receptor TrkA have been shown to cause congenital anhidrosis and pain insensitivity (82, 113).
The highest levels of mature NGF in the CNS are found in the hippocampus, which supplies trophic support for septal and basal forebrain cholinergic neurons through retrograde transport (97, 173). In these neurons, NGF regulates the expression of cholinergic markers (eg, choline acetyltransferase) needed for acetylcholine synthesis and neurotransmission (136). The atrophy of cholinergic neurons and memory dysfunction seen after axotomy of basal forebrain neurons (ie, with lesion of fornix) can be prevented by providing exogenous NGF to these neuronal cell bodies (57, 71, 99). Recent work from Salehi et al has also provided evidence for decreased retrograde transport of NGF from hippocampus to basal forebrain in the triosomy 16 mice that display an Alzheimer’s‐like phenotype (160). Although the NGF−/− mice die in the postnatal period (43), mice heterozygous for the NGF gene (NGF+/−) are viable, showing decreased cholinergic innervation of the hippocampus and deficits in memory acquisition (39). Beyond proving that NGF is needed throughout life, this haplotype insufficiency for NGF indicates that partial depletion of the ligand can alter neuronal function in vivo. These and other studies have provided support for the notion that exogenous NGF could be used as a treatment for Alzheimer’s disease. This issue is discussed in detail in the accompanying article by Blesch (16). Effects of NGF and other neurotrophins on myelination is discussed in the accompanying article by Rosenberg et al (155).
BDNF and NT‐4/5. In the PNS, BDNF is a trophic factor for sensory neurons of both neural crest (eg, DRG neurons that mediate mechano‐reception) and ectodermal placode origin (eg, nodose ganglion neurons that innervate viscera) (8). NT‐4/5 binds to the same TrkB receptor as BDNF, and, consequently, there is a significant overlap between the actions of these two factors in the PNS (81). In contrast to knockouts for the other neurotrophins or the cognate Trk receptors, NT‐4/5−/− mice show no obvious behavioral deficits and have normal life spans (42, 120). However, a closer inspection of NT‐4/5−/− animals has shown abnormalities in innervation of sympathetic ganglia, loss of vagal afferents to enteral mechanoreceptors and decreased tolerance to morphine (58, 154, 166).
By and large, the CNS sets BDNF and NT‐4/5 apart, as BDNF is more widely expressed in the CNS and shows regulated secretion in response to activity. BDNF knockout mice, both homozygotes and heterozygotes, show reduced long‐term potentiation (LTP) (102), the cellular correlate of long‐term memory, suggesting a role for BDNF and its TrkB receptor in synaptic plasticity. Exogenously applied BDNF has been shown to facilitate induction of LTP, particularly the transition to long‐lasting LTP that is protein synthesis‐dependent (103). These and other studies have led to the hypothesis that BDNF plays a critical role in the activity‐dependent neuroplasticity underlying learning and memory (124). Neurotrophins, including BDNF, enhance neurotransmission at the neuromuscular junction, and postsynaptic sources of BDNF and NT‐4/5 facilitate synaptogenesis in neuron/muscle cocultures (122, 171, 183, 190). Recent studies further implicate BDNF with the cognitive deficits associated with Alzheimer’s disease (48, 73). Trisomy 16 mice, which provide a mouse model of Down’s syndrome with overexpression of amyloid precursor protein, show abnormal BDNF signaling, and restoration of BDNF signaling by expression of full‐length TrkB prevents neuronal apoptosis in cortex (47) Together, these data suggest that BDNF plays a prominent role in both the development and function of the CNS. This is not to say that NT‐4/5 is without any CNS functions that are relevant to pathologies of the brain and spinal cord. Injection of NT‐4/5 into the marginal zone of embryonic rodent brain results in neuronal heterotopias through a TrkB‐dependent mechanism; surprisingly, NT‐4/5 shows more than 10‐fold greater propensity to induce heterotopias than does BDNF (21).
The propeptide sequence of endogenous BDNF sends this protein uniquely into a secretory pathway with activity‐dependent release of BDNF‐containing secretory vesicles (176). The propeptide regions of NGF, NT‐3 and NT‐4/5 are argued not to provide this level of directed secretion, although stimulus‐dependent release of NGF and NT‐3 has been demonstrated (19, 29, 78, 104, 189). Pro‐BDNF requires sorting by carboxy‐peptidase E to yield mature peptide in the regulated secretory pathway (123), while furin cleaves the proneurotrophins in the constitutive pathway [for reviews, see (119, 176)]. A single nucleotide polymorphism in the human BDNF gene has been shown to alter its regulated secretion such that BDNF with methionine rather than valine at residue 66 only shows constitutive release. Individuals carrying this polymorphism show evidence of altered memory acquisition (48). Activity‐dependent secretion of BDNF at the synapse has been demonstrated in several different neuronal systems, including cortical neurons and the neuromuscular junction [for a review, see (176)]. Locally released BDNF enhances synaptic efficacy both through effects locally at, or adjacent to, the synapse and through retrogradely signaling to the cell body (124). For example, BDNF has been shown to both regulate localized mRNA translation in dendrites and alter the delivery of mRNAs into dendrites (1, 177, 195). Localized effects of BDNF and the other neurotrophins are discussed in more detail in subsequent sections.
NT‐3. NT‐3 promotes survival and neurite outgrowth of the large‐diameter proprioceptive neurons of the DRG that innervate stretch and tension receptors in muscle and joints (50, 53). NT‐3 also has trophic actions on neurons of the nodose ganglia, sympathetic ganglia, Remak’s ganglia, ciliary ganglia, trigeminal mesencephalic nucleus and spiral ganglia (42, 117). As NT‐3 binds to all Trk receptors, some of the biological effects of NT‐3 can occur through binding to Trks other than TrkC. Indeed, sympathetic neurons of the superior cervical ganglion (SCG) require both NT‐3 and NGF for survival during development [for a review, see (67)]. NT‐3 supports survival and axonal outgrowth from SCG neurons as their axons are traversing toward their target of innervation; these SCG neurons switch from NT‐3 to NGF responsiveness upon reaching their targets of innervation (107). Interestingly, the effect of NT‐3 on sympathetic neurons is through TrkA rather than its preferred TrkC binding partner. Thus, the promiscuity of NT‐3 in its interactions with Trk family members has clear biological relevance during development. Beyond its effects on survival and neurite outgrowth, NT‐3 has been found to be important for keeping neural crest derivatives in a proliferative state during early development (52). NT‐3−/− mice die within a few weeks after birth, and show severe sensory and sympathetic neuron loss with abnormal limb movement (42). Crossing neurotrophin knockout animals with mice that have altered expression of Bcl‐2 family proteins, which affords neurotrophin‐independent neuronal survival during development, has led to the discovery of new activities for some neurotrophins. For NT‐3, NT‐3−/−Bax−/− mice show altered central connectivity of proprioceptive neurons in the spinal cord, indicating that NT‐3 plays a role in central patterning for proprioception, in addition to survival of proprioceptive DRG neurons (144).
Proneurotrophins. These precursors to mature neurotrophins were known to exist for quite some time, but biological activity of the proneurotrophins was only recently discovered (110). In general, the actions of the proneurotrophins are antagonistic to those of the mature neurotrophins [for a review, see (76)]. The proneurotrophins preferentially bind to p75NTR, but not all p75NTR expressing cells are sensitive to proneurotrophins; expression of the neurotensin receptor sortilin is apparently needed for proneurotrophins to induce biological effects (140). The binding characteristics of proneurotrophins to Trks has not been as extensively studied as those of the mature neurotrophins, and Fayard et al have reported that pro‐BDNF can bind to TrkB (54). Thus, the proneurotrophins may hold many surprises just as the p75NTR has over the years (see below). Nonetheless, currently available evidence indicates that the antagonistic effects of the proneurotrophins have pathophysiological relevance for human disease and injury. Axotomy through lesion of the internal capsule increases levels of pro‐NGF, resulting in apoptosis of corticospinal neurons through binding to p75NTR (74). Pro‐BDNF similarly induces neuronal apoptosis though the p75NTR/sortilin receptor complex (175). Actions of the proneurotrophins are not limited to neurons. Indeed, work from the Yoon group has shown that induction of pro‐NGF after spinal cord injury kills oligodendrocytes (11). Previous work indicated that mature NGF can induce apoptosis in cultured oligodendrocytes and transfection of TrkA prevented NGF from killing these glial cells (196). It should be noted that other studies have demonstrated p75NTR signaling in oligodendrocytes but did not report apoptotic effects of NGF or pro‐NGF (2, 109). Analyses of rodent and human tissues indicates that pro‐NGF, rather than the mature NGF peptide, is the predominant form in the brain, and pro‐NGF appears to be increased in Alzheimer’s disease as well as patients with mild cognitive impairment (51, 146). It will be interesting to see if the proneurotrophins play any role in the primary and metastatic CNS tumors that are discussed in the accompanying review by Krüttgen et al (105).
The antagonistic functions of mature neurotrophins and proneurotrophins extend beyond cell death. As noted above, mature BDNF plays a central role in synaptic strengthening for LTP (55, 102, 103, 145). Pro‐BDNF was recently shown to weaken synaptic strength, resulting in long‐term depression (LTD) (187). p75NTR also appears to play a role in dendritic growth as p75NTR−/− mice have increased dendritic spine complexity and overexpression of p75NTR decreases dendritic spine complexity (198). As discussed below, p75NTR has assumed a major role in the failed regeneration of CNS axons, suggesting that there could be an overlap between the mechanisms for axonal growth and spine morphogenesis. As Trk induces signals that generally counter p75NTR’s effects (182), activation of Trk may be one means to overcome the effects of proneurotrophins on synaptic activity. Extracellular cleavage of pro‐BDNF by activity‐dependent stimuli tips the balance toward the synaptic strengthening functions of neurotrophins (143).
INTRACELLULAR EFFECTORS FOR THE NEUROTROPHINS
Neurotrophins exert their biological actions by binding to two different classes of transmembrane receptors, the Trk family of receptors and p75NTR. Both receptors can trigger downstream signaling pathways to exert the biological effects of neurotrophins, proneurotrophins and other relevant ligands. One can broadly divide these pathways into Trk‐mediated signaling, which is generally growth‐promoting and prosurvival, and p75NTR‐mediated signaling, which is generally proapoptotic and growth‐inhibiting (Figure 1).
Figure 1.
Antagonistic functions of the neurotrophin receptors, Trk and p75NTR. Summary of the directly antagonistic biological outcomes of ligand binding to Trk or p75NTR proteins along the neuronal cell surface is outlined. Mature neurotrophins are the preferred ligand for TrkA, TrkB and TrkC with p75NTR facilitating interactions with Trks (see text). Although all of the mature neurotrophins will also bind to p75NTR, proneurotrophins apparently use p75NTR as their preferred receptor but also require the presence of sortilin to generate an intracellular effect. The myelin inhibitor proteins, MAG, OMgP and Nogo, also signal through a multiprotein receptor complex consisting of Nogo‐R, Lingo‐1 and p75NTR. This ligand–receptor complex is best characterized for inducing axonal retraction or preventing axonal regrowth/regeneration in the CNS. LTD = long‐term depression; LTP = long‐term potentiation; MAG = myelin‐associated glycoprotein; NTR = neurotrophin receptor; NTs = neurotrophins; OMgP = oligodendrocyte‐myelin glycoprotein; Trk = tropomyosin‐related kinase.
The first member of the Trk family was discovered as an oncogene in which tropomyosin was fused to the kinase domain of TrkA (129). TrkA was later identified as an NGF receptor (94). The Trk proteins, TrkA, TrkB and TrkC, share the greatest degree of homology in their intracellular regions that possess tyrosine kinase activity. The extracellular regions that confer ligand‐binding specificity are the most variable (81). NGF preferentially binds to TrkA, BDNF and NT‐4/5 bind to TrkB, and NT‐3 binds to TrkC (18). As mentioned above, NT‐3 is promiscuous and can bind to TrkA and TrkB under some conditions. Expression of p75NTR appears to allow NT‐3 to discriminate its preferred TrkC from the other Trk receptors (135). These different Trk receptors are expressed in both primary neurons and neuronal cell lines and targeted mutation of trkA, trkB and trkC genes in mice disrupts neuronal development consistent with a loss of neurotrophin action (7).
Many of the signaling mechanisms activated by the Trks converge upon the nucleus to alter gene expression programs. Downstream signaling has been best characterized for TrkA, but signals activated by TrkB and TrkC appear generally similar (81). NGF binding to TrkA causes receptor dimerization leading to autophosphorylation of tyrosine residues within its kinase domain (27, 157). Subsequent phosphorylation of other tyrosine residues promote signaling by creating docking sites for proteins with Src homology 2 motifs (SH2) (121, 141, 170). Activation of the Ras/Rap–mitogen‐activated protein (MAP) kinase and phospholipase C γ (PLCγ) pathways can trigger changes in gene expression by direct or indirect activation of transcription factors. Downstream effectors for these two pathways include the extracellular signal‐regulated kinases 1 and 2 (Erk 1/2) and protein kinase C (PKC) isoforms, including the atypical PKCs (199). Trk‐dependent activation of phosphoinositoyl‐3 kinase (PI3K) can also regulate transcription through downstream regulation of Akt activity (93). However, this is more frequently considered a prosurvival pathway, with Akt preventing activation of proapoptotic members of the Bcl2 family (60). In addition to transcriptional regulation, both the Ras–MAP kinase and PI3K pathways can regulate activity of the translational machinery (66, 158). Likewise, each of the Trk‐activated pathways can have localized effects in the cytoplasm by regulating activity of proteins involved in synaptic function, cytoskeletal remodeling and bioenergetics (see below). Additionally, transcriptional regulation through Trk signaling can occur by epigenetic modifications of chromosome‐binding proteins, in addition to the classic transcription factor‐mediated events outlined above (34).
p75NTR, the first neurotrophin receptor to be identified (86, 151), is a transmembrane glycoprotein that shares a high degree of homology with members of the TNF receptor superfamily (76). Cysteine repeats in the extracellular domain confer relatively equal binding affinity to all members of the neurotrophin family (36). For mature neurotrophin interaction to the p75NTR, opposite cellular effects occur depending upon whether or not a cognate Trk receptor is present. For example, cells expressing both p75NTR and TrkA display a much higher binding affinity for NGF than under circumstances where either receptor is expressed alone (37). Ligand binding to p75NTR can potentiate TrkA autophosphorylation at subsaturating NGF concentrations and this appears to be dependent on the relative levels of p75NTR and TrkA (10, 28, 126, 180, 181). In stark contrast to these synergistic effects upon Trk signaling, p75NTR has also been shown to mediate neurotrophin‐induced cell death (31, 150). This is exemplified in circumstances in which p75NTR is expressed in the absence of an appropriate neurotrophin Trk receptor. For example, BDNF can promote apoptosis in primary sympathetic neurons that express p75NTR and TrkA but not TrkB (6), and endogenous NGF induces death of developing chick retinal neurons that express p75NTR and TrkB but not TrkA (59). NGF has been shown to promote cell death of mature oligodendrocytes, which express p75NTR but not TrkA (31), and introduction of TrkA negates the p75NTR‐dependent cell death seen with mature NGF (196). Thus, the survival vs. death decisions by neurotrophins rely critically upon matching the ligand with the appropriate Trk receptor.
The story of p75NTR has held many surprises since its first discovery as “the NGF receptor” and then the realization that it contained no clearly recognizable signal transducing domains. With the discovery of Trks, attention waned from the possibility that p75NTR could signal on its own. In addition to the effect of mature neurotrophins binding to p75NTR, proneurotrophins preferentially bind to p75NTR and CNS molecules that actively block axonal outgrowth use p75NTR as a signaling coreceptor. These ligands activate p75NTR signaling that in some cases is similar to those signals utilized by the related TNF receptors (98), while in other cases the signaling pathways appear unique to p75NTR, at least for the present time. Ligand binding to p75NTR can activate the c‐Jun N‐terminal kinase and NFκB transcription factor (14, 30, 31). Ligand‐dependent cleavage of p75NTR was very recently shown to provide a means for the intracellular domain (ICD) of p75NTR to signal (96). This solved a mystery of how expression of just the p75NTR ICD can induce cell death (128) and of the functional role of neurotrophin receptor interacting factor (NRIF), a zinc‐finger protein that was cloned as a p75NTR binding protein (32). Mature BDNF and pro‐BDNF can induce cleavage of p75NTR through γ‐secretase with release of p75NTR ICD, nuclear translocation of NRIF and apoptosis in sympathetic neurons (96). p75NTR has also provided some resolution to the mystery of how the myelin‐associated glycoprotein (MAG), oligodendrocyte‐myelin glycoprotein (OMgP) and Nogo, myelin proteins that inhibit axonal outgrowth in the CNS (56), can transduce intracellular signals. These myelin proteins bind to a multisubunit receptor complex that uses p75NTR as its signal transducer (132) [for a review, see (9)]. This receptor complex consists of the Nogo receptor (Nogo‐R), LINGO‐1 and p75NTR. The Rho‐guanosine diphosphate (GDP) dissociation inhibitor α (Rho‐GDIα) binds to the ICD of p75NTR upon MAG’s interaction with the cell surface and shifts activity of the small G‐protein Rho toward activation to favor F‐actin depolymerization (192). Mature neurotrophins binding to p75NTR have the opposite effect, shifting the balance of Rho activity toward inhibition (193). This could place p75NTR as a central determinant in the balance of axonal microfilament polymerization vs. depolymerization by intracellularly changing Rho activity based upon what ligands/receptor partners p75NTR is interacting with extracellularly (see Figure 2B).
Figure 2.
Local tropic and trophic effects of the neurotrophins. Schematic summarizing the effects of mature neurotrophins (NT) and proneurotrophins (pro‐NT) at the synapse (A) and growth cone (B) is shown. Anatomic designations are shown in gray italicized text. Symbol identities are designated in the legend. Green dashed lines illustrate intracellular effects of Trks and red dashed lines illustrate effects of p75NTR. A. Presynaptic effects of the NTs include facilitating release of neurotransmitters (a) and activating localized translation to generate new proteins (c). Postsynaptically, NTs can modify synaptic proteins through phosphorylation (a), antagonize effects of p75NTR to favor actin filament polymerization (b) and activate localized protein synthesis to generate new proteins (c). Although pro‐NTs have been shown to play a role in long‐term depression with synaptic weakening, the exact mechanism of this is not clear. In other systems, signaling through p75NTR has been shown to favor actin filament depolymerization (b). p75NTR may also signal directly to other pre‐ or postsynaptic components (?) to repress synaptic strength. Signals through Trks are retrogradely transmitted to the cell body, but it is not clear whether p75NTR generates any retrograde signals in dendrites or axons. Note that neither activity‐dependent nor neurotrophin‐dependent effects on neurotrophin release are represented in this schematic; refer to text for information on these stimuli for regulated release of neurotrophins. B. In growing axons, NTs can modify effector proteins to support axonal growth [eg, microtubule‐associated proteins, (a)], facilitate actin filament polymerization (b) and modulate localized protein synthesis (c). Signaling through p75NTR, particularly for the myelin inhibitor proteins (MAG, OMgP and Nogo), has been shown to favor actin filament depolymerization with growth cone collapse (b) and destabilization of microtubules (c). Antagonistic signals from p75NTR and Trks shown in this terminal axon would actively induce turning upward toward the NT source and away from sources of pro‐NT, MAG, OMgP and Nogo. MAG = myelin‐associated glycoprotein; NTR = neurotrophin receptor; OMgP = oligodendrocyte‐myelin glycoprotein; Trk = tropomyosin‐related kinase.
The intracellular signaling pathways that are activated by Trks and p75NTR are shared by many different ligand–receptor systems. The biological response to a specific ligand can be determined by the timing and magnitude of downstream signaling events as well as the combination of signals activated. For example, in the PC12 cell line, NGF induces neuronal differentiation while epidermal growth factor (EGF) is mitogenic. This distinction is determined by the kinetics of activation of the Erk 1/2 [see (105)]. EGF causes transient activation of Erk 1/2 through activation of the G‐protein Ras, while NGF activation of Erk 1/2 lasts for hours and uses both Ras and Rap (68, 92, 197). Despite the fall in Erk 1/2 activity after initial exposure to NGF, a continued basal level of Trk activity (and downstream signals) is required to drive transcription in cells that need neurotrophins for survival and phenotypic maintenance (33).
LOCAL TROPIC AND TROPHIC ACTIVITIES OF THE NEUROTROPHINS—CONSIDERATIONS FOR INJURY AND PLASTICITY
Mechanistically, the effects of the neurotrophins can be divided into local effects that occur adjacent to points of release of the ligands (eg, at the synapse or growth cone) and systemic or whole cell effects that are initiated by retrograde signaling to the cell body and nucleus. Retrograde signaling by internalized Trk receptors is particularly relevant for transcriptional responses to localized sources of neurotrophins. p75NTR is also internalized, but this process is much slower than that seen with the Trks and the full biological relevance of internalized p75NTR has yet to be demonstrated (20). Here, we will focus on recent advances in the localized responses to neurotrophins. We refer the reader to Zweifel et al for an excellent review on the topic of retrograde signaling (201). To exert their local effects, neurotrophins act upon existing macromolecules to alter protein function and cytoskeletal organization. Additionally, the neurotrophins can alter protein levels by directly modulating activity of the protein synthesis machinery that is concentrated near dendritic spines and within growth cones of axons (Figure 2). As discussed below, a surprising finding with translational regulation is the specificity that the protein synthesis machinery exhibits for individual mRNAs.
Local effects of neurotrophins in synaptic transmission and plasticity. Neurotrophin expression can be regulated by neuronal activity, and increase in neurotrophin levels has been shown to facilitate neurotransmission [for reviews, see (119, 124)]. Analyses of mice after kainic acid‐induced seizures suggested a local effect of neurotrophins with release of BDNF into the neuropil surrounding hippocampal dendrites (185). Using hippocampal slice preparations, Kang and Schuman showed that BDNF and NT‐3 can enhance synaptic efficacy through local effects at the synapse (89, 90, 91). Application of exogenous BDNF or NT‐3 to the developing neuromuscular junction also acutely enhances neurotransmitter release (122). For BDNF, this occurs through influx of calcium into the presynaptic cell and requires intracellular cyclic adenosine monophosphate (cAMP) (171). In contrast, NT‐3 induces release of intracellular calcium stores as well as activations of PI3K with resultant generation of free inositol triphosphate and calcium/calmodulin kinase (75, 194). Long‐term changes in synaptic neurotransmission at the neuromuscular junction require internalization of NT‐3 with activation of Akt, target of rapamycin and new protein synthesis (84). Localized activation of postsynaptic and presynaptic protein synthesis has been shown to modulate synaptic efficiency in several different neuronal systems [for recent reviews, see (148, 163, 184)]. In the neuromuscular junction, this BDNF‐triggered protein synthesis occurs directly within the axon terminus (200). Neurotrophins can directly regulate translation of specific mRNAs in dendrites whose products have been associated with learning and memory (1, 177, 195). With limited quantities of proteins derived from primary neuronal cultures and inefficiency of metabolic labeling approaches, the study of translational activation has not progressed at the same rates as analyses of changes in neuronal gene expression, where PCR can be used to amplify signals. Schratt et al addressed this technical limitation using a polysomal RNA fractionation approach to identify previously unrecognized mRNA targets for translational regulation by BDNF (162). Additional studies are needed to determine how many of these translationally regulated mRNAs will be relevant for localized effects of the neurotrophins. Although there has not been a direct link between neurotrophin‐regulated pre‐ or postsynaptic protein synthesis and human disease, brain tissue from Alzheimer’s disease show alterations in the translational machinery, suggesting that protein synthesis could be hindered in diseased neurons (45, 80). This, combined with altered neurotrophin levels, could compromise presynaptic and postsynaptic protein levels (and synaptic function) in neurodegenerative diseases.
Synaptic plasticity has been associated with growth of neuronal processes generating increased dendritic spine complexity. Interestingly, signaling through p75NTR−/− was recently shown to decrease dendritic spine complexity (198). It is not clear whether the ligand for this effect is mature or proneurotrophins; however, as noted above, proneurotrophins induce LTD that is generally associated with a decrease in synaptic strengthening (187). Despite this effect, pro‐BDNF can be converted to mature BDNF extracellularly through tissue plasminogen activator (tPA)/plasmin facilitating protein synthesis‐dependent late‐phase LTP in mouse hippocampus (143). Balance between Trk and p75NTR signaling could be a critical determinant of synapse structure, with Trk signaling favoring increased dendritic spine complexity and p75NTR favoring decreased dendritic spine complexity. In growing axons, activation of apoptotic pathways can rapidly trigger retraction of growth cones (26). Such local effects of apoptotic pathways could underlie the effect of p75NTR on dendritic spines. In cultures of basal forebrain neurons, the balance between apoptotic signaling through p75NTR and survival signaling through TrkA is determined by activity levels of PI3K and Ras/Rap–MAP kinase pathways (182).
Alterations in dendritic spine complexity have been demonstrated in several human neurodevelopmental disorders (4, 95, 152). Post‐mortem analyses of brains from patients with Rett syndrome, an X‐linked disorder that is most frequently caused by mutation of the methyl‐CpG binding protein (MeCP2) (3), show a reduction in dendritic arborization with decreased numbers of dendritic spines in frontal and motor cortex (4, 5, 12), and mice with targeted disruption of the Mecp2 gene display similar neuropathology (61). MeCP2 binds to methylated regions of chromosomes and functions as a transcriptional repressor by interacting with chromatin remodeling complexes including histone deacetylases (118, 138). MeCP2 was recently shown to differentially repress one of the BDNF gene promoters and neuronal activity triggers decrease in CpG island methylation with derepression of the BDNF gene (40, 130). Impaired regulation of BDNF expression may be critical in the pathogenesis of the neuronal lesion in Rett syndrome. The pathological effects of dysregulated BDNF expression in Rett syndrome could be further exacerbated by other neurotrophins or proneurotrophins acting through p75NTR to alter spine morphogenesis. Overexpression of a BDNF transgene was recently shown to improve survival and neurophysiological measures of neuronal dysfunction in the MeCP2 mutant mice that have provided a mouse model of Rett syndrome (35). Thus, activity‐dependent regulation of BDNF expression could indeed alter dendritic complexity in human neurodevelopmental disorders. Although not associated with neurotrophins, at least thus far, the increase in dendritic spine complexity seen in fragile X mental retardation is thought to be caused by loss of a translational suppressor that localizes to dendrites, the fragile X mental retardation protein (70). This suggests that a delicate balance in protein synthesis within dendrites is required for appropriate dendritic spine morphogenesis in human development.
Tropic effects of neurotrophins in development and regeneration. The interaction between Trk and p75NTR signaling also plays a role in axonal outgrowth during development and regeneration. Localized sources of neurotrophins serve as pathfinding cues, providing a tropic source for developing and regenerating axons through Trk signaling. In embryonic development, target tissues can serve as a localized source of neurotrophins. In injured peripheral nerves, increased synthesis and release of NGF by axotomized Schwann cells may play a role in guiding axons into degenerating distal stump of the nerve (77). Other neurotrophins and non‐neurotrophin trophic factors undoubtedly contribute to successful regeneration in the PNS (164, 191). Also, the potential role of proneurotrophins needs to be considered. In the CNS, myelin proteins and proteoglycans expressed within glial scars after injury actively prevent regeneration (56, 69). Although axonal regeneration is rarely successful in the CNS, neurotrophins have been used as one means to lure axons into the nonpermissive environment of the adult CNS (22, 101, 108). As indicated previously, signaling through p75NTR provides the CNS myelin inhibitory molecules with a mechanism to block axonal growth (9). This inhibition of growth appears to be a local effect on the growing axon, at least initially, rather than a systemic affect generated at the cell body.
In cultured neurons, the growth‐promoting or attractant effects of localized sources of neurotrophins induce turning of growth cones and sprouting along axon shafts (63). Both of these events require signaling to the axonal cytoskeleton, particularly the microfilaments that are required for growth cone motility (64). Work from several laboratories has pointed to a role for localized protein synthesis in pathfinding for developing axons (25, 134, 149, 188). As adult mammalian axons also have the capacity to locally synthesize proteins (179), this mechanism is also relevant for axonal regeneration. In retinal and motor neurons, application of BDNF to growth cones triggers intracellular signals that converge upon the protein synthesis machinery. Blocking BDNF’s activation of localized protein synthesis prevents axonal turning in response to this ligand (25, 134). Focal sources of neurotrophins can also modulate the levels of mRNAs in regenerating sensory axons that are needed for growth cone motility and responses to injury (147, 186). Some repellant cues for the growth cone similarly require localized protein synthesis; other repellant stimuli activate both protein synthesis and proteolysis, while some just trigger proteolysis in the growth cone (25). The proteolytic events are triggered by activation of apoptotic signaling in the growth cone, including activation of the stress‐activated kinase p38MAPK and caspase 3 (26). On the other hand, the turning response to attractant cues requires activation of Erk 1/2 and calcium signaling (26, 134). Thus, whether a stimulus invokes attraction or repulsion is likely determined by the balance of intracellular signals that are activated locally in the terminal axon. The recent history of what stimuli the growing axon has encountered also plays a role in determining its response to subsequent stimuli (44, 134, 149).
Activation of p75NTR by MAG, OMgP and Nogo inhibitors prevents axonal outgrowth. In cultured neurons, localized sources of MAG induce axonal retraction or turning (165). MAG induces intramembranous cleavage of p75NTR similar to the proneurotrophins activating Rho and downstream signals that can favor actin depolymerization (46). Furthermore, MAG blocks microtubule assembly through downstream activation of Rho kinase (133). Primary sensory neurons and cerebellar granular cells can be coaxed to extend axons across purified MAG and biochemical preparations of CNS myelin if they are first primed with neurotrophins (22, 165). Developing neurons see MAG as an attractant cue for growth because their levels of cAMP are higher than the cAMP levels of adult neurons (23). This elevation of cAMP results in the synthesis of polyamines through increased arginase levels and activation of the transcription factor cAMP‐response element‐binding protein (CREB) (24, 65). Activation of CREB is sufficient to overcome the effects of myelin inhibitors in adult neurons (65). Thus, stimulus history can alter how an axon interprets guidance cues that work through p75NTR, but this requires a transcriptional response in the cell body. Interestingly, the attractant responses of NGF, BDNF, NT‐4/5 and NT‐3 can be modified by intracellular levels of cyclic nucleotides. Decreases in cAMP for NGF, BDNF and NT‐4/5, and cGMP for NT‐3 convert these tropic factors from attractant to repulsant cues [for a review, see (169)]. In retrospect, this shift could indeed result from altering the balance of Trk to p75NTR signaling within the growth cone. Curiously, cAMP signaling also regulates the BDNF‐dependent formation of dendritic spines (85), pointing to overlapping mechanisms of axonal and dendritic growth.
Although the above mechanisms hold great potential for facilitating regenerative growth after spinal cord injury and stroke, there are not yet obvious examples of axonal pathfinding or repair deficits that have been shown to result directly from alterations in Trk or p75NTR signaling. However, searches for proteins that bind the p75NTR’s ICD have provided some insight into mechanisms underlying human neurodevelopmental disorders. Salehi et al initially showed that a novel melanoma‐associated antigen gene (MAGE) family member, termed NRAGE, binds to the juxtamembrane domain of p75NTR. NRAGE binding to p75NTR appears to block p75NTR–Trk interactions, favoring p75NTR‐dependent apoptosis (161). Other MAGE family members, including necdin, bind p75NTR and increase neuritogenesis through Trk‐independent means (174). Notably, four members of the MAGE family (Necdin, MAGE‐G1, MAGE‐L1 and MAGE‐H1) map to the imprinted region on chromosome 15q that is deleted in Prader–Willi and Angelman syndromes (17, 83, 100, 125, 172), and mice lacking the paternally expressed necdin gene show some characteristics of Prader–Willi syndrome, in conjunction with deficits in axonal growth, including altered fasciculation of processes in white matter tracts, pathfinding and target innervation (111, 142). Although the exact mechanism by which p75NTR/necdin interactions are connected to axonal outgrowth remain unclear, these findings certainly imply that altered p75NTR signaling can contribute to the axonal outgrowth abnormalities seen in human neurodevelopmental disorders. Necdin and MAGE‐G1 have been shown to repress transcriptional activity of the apoptosis‐promoting protein E2F1, but the data suggest that this is exclusive of p75NTR–MAGE protein interaction (106). Necdin interacts with other proteins in the cytoplasm that have been associated with cytoskeletal modulations of axonal outgrowth (111), which may provide a more direct link between p75NTR/necdin interaction and axonal growth. Regardless of exact mechanisms, the MAGE family’s interaction with p75NTR represents another point where proapoptotic and growth‐promoting activities of the neurotrophin receptors intersect.
CONCLUSIONS AND PERSPECTIVE
Survival‐ and growth‐promoting activities of the neurotrophins in the CNS and PNS have generated much interest in therapeutic applications for these growth factors in many different neurological diseases and injury states. Although systemic treatment with neurotrophins has generally proven ineffective, the accompanying reviews by Sahenk and Blesch emphasize high promise for the use of localized neurotrophin therapy for neuropathies and neurodegeneration (16, 159). However, there is still much to learn about the mechanisms of actions of the neurotrophins. In this short review, we have tried to emphasize the overlapping mechanisms that the neurotrophins use to support survival, growth and synaptic plasticity in different neuronal populations. Common intracellular mechanisms could prove beneficial in planning treatments with exogenous neurotrophins. For example, activity‐dependent increase in BDNF and NT‐3 expression in sensory neurons results in an enhanced regeneration capacity after PNS nerve injury by priming the neurons for increased growth (137). Thus, animals with decreased activity may have an overall poorer regenerative response to axotomy. It will be important to determine whether this observation can be extended to the CNS and if mechanisms of traumatic injury can be extrapolated to cellular injuries with neurodegeneration. Intracellular mechanisms triggered by the neurotrophins are able to overcome at least some components in the inhibitory environment of the CNS white matter (22). Overlapping intracellular mechanisms for the neurotrophins may also exacerbate the pathophysiology of disease states accompanied by decrease in endogenous neurotrophins. The secondary effects on endogenous neurotrophins also warrant some consideration in planning neurotrophin therapies as activity‐dependent release of endogenous neurotrophins can be regulated (29, 104, 189). This effectively provides a feed‐forward mechanism to facilitate neuronal survival, growth and plasticity. With the discovery of antagonistic effects of proneurotrophins and p75NTR signaling, consideration must also be given to how to overcome these “bad actors.”
ACKNOWLEDGMENTS
The authors thank Drs. Armin Blesch, Jonah Chen, Alex Kruttgen, and Zarife Sahenk for constructive criticisms on this manuscript. Work on related topics has been supported by R01‐HD037874 (NCS), R01‐NS041596 and R01‐NS049041 (JLT), and programmatic funds from the Nemours Foundation (NCS and JLT).
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