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Review
Nature Neuroscience  2, 213 - 217 (1999)
doi:10.1038/6310

Hepatocyte growth factor, a versatile signal for developing neurons

Flavio Maina & Rüdiger Klein

European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69117 Heidelberg, Germany

Correspondence should be addressed to Flavio Maina
maina@embl-heidelberg.de
or Rüdiger Klein
klein@embl-heidelberg.de
Here we summarize recent findings on the biology of hepatocyte growth factor (HGF, also known as scatter factor), focusing on its effects on developing neurons. HGF is both a chemoattractant and a survival factor for embryonic motor neurons. In addition, sensory and sympathetic neurons and their precursors respond to HGF with increased differentiation, survival and axonal outgrowth. The broad spectrum of HGF activities and its observed synergy with other neurotrophic factors suggest that the major role of HGF is to potentiate the response of developing neurons to specific signals.
The development of the central (CNS) and peripheral (PNS) nervous systems is a multi-step process driven by the finely tuned effects of an array of factors which influence the fate of neurons and their precursors. Many of these factors have effects not only on neurons but also on adjacent non-neuronal cells and on cells in target tissues, distant from the neuronal cell body. Hepatocyte growth factor (HGF, also known as scatter factor) is one example of such a pleiotropic factor which is able to induce a variety of responses in development and in pathological situations. HGF is a polypeptide growth factor that acts by binding to the Met tyrosine kinase receptor. HGF was originally identified as a molecule that could trigger motility (hence the name 'scatter factor'), proliferation and morphogenesis in a variety of epithelial cell types (reviewed in 1). It was later found to be involved in organ regeneration, angiogenesis and tumor invasion2, 3, and experiments in chick embryos suggested that HGF might also play a role during early steps of neuronal induction4, 5. Targeted disruption of either the hgf or the met locus in mice confirmed the importance of HGF signaling in development; mice lacking either HGF or its receptor die during embryogenesis, with defects in placenta, liver and muscle6, 7, 8, 9. This early lethality has made it difficult to study the role of HGF in later stages of development; in one study, however, the placental defect was bypassed by replacing the endogenous met gene with a signaling mutant of met, thereby revealing a requirement for Met in late myogenesis for secondary muscle fiber formation9.

HGF has also been proposed to have additional roles in the development and function of the nervous system. Both HGF and Met are expressed during brain development, and their expression persists in the adult10, 11, 12, 13. HGF promotes neurite outgrowth from neocortical explants and enhances the number of tyrosine hydroxylase (TH)-positive neurons in vitro14. Thus, HGF may mediate neurotrophic functions during neurogenesis, that is, promoting survival and/or maturation of CNS neurons in vivo. Although analysis of hgf and met mutant mice have contributed greatly to understanding of HGF and Met functions during development of the nervous system, the early lethality of these mutants implies that conditional mutagenesis will be required to uncover additional roles for HGF signaling in adult animals.

HGF and Met are expressed not only in neurons but also in nonneuronal cells within the nervous system, including microglia15 and Schwann cells, for which HGF is a mitogen16. HGF therefore signals to a much broader range of cells than, for example, the neurotrophins, which mainly act on neurons; the multiple effects of HGF on interdependent cell types such as neurons and glia suggest that HGF may affect neurons both directly via Met receptors on neurons themselves and indirectly via glial cells (perhaps by modulating their production of other neurotrophic factors). From the recent work on HGF summarized in this review, there emerges a complex picture of paracrine and autocrine functions during the development of different types of neurons.

HGF is a chemoattractant for motor neurons
Migrating motor axons are guided to their target muscles by both repellent and attractant chemotropic factors. For instance, the mesenchyme and the sclerotome, but not the dermamyotome, induce axonal outgrowth from spinal cord cultures. In a search for diffusible guidance factors for developing spinal motor axons, HGF was found to be a limb-mesenchyme-derived chemoattractant17. Not only can HGF induce neurite outgrowth, but the outgrowth that is induced by forelimb mesenchyme can be blocked by HGF-neutralizing antibodies, suggesting that HGF is a major component of the naturally occurring activity. Consistent with this idea, forelimb mesenchyme derived from hgf mutant embryos is unable to induce neurite outgrowth17. This experiment alone is not definitive, because HGF is also required for myoblast migration8, 9, and so the mutants—which lack muscle precursors—might be lacking some neurite-outgrowth-promoting factor secreted by the muscle. This possibility has been ruled out, however, by the demonstration that forelimb mesenchyme derived from met mutant embryos, which also lack migrating muscle precursors in their limbs, can still induce neurite outgrowth17. These experiments confirm that HGF itself, secreted by the limb mesenchyme, is responsible for the observed neurite outgrowth. To determine whether HGF was a chemoattractant or simply a growth-promoting factor, two ventral neural tube explants were exposed in tandem to a graded source of HGF. The ability of HGF to orient the trajectories of emerging axons in these experiments is consistent with HGF being a chemoattractant molecule17.

The defects observed in hgf and met mutant mice are consistent with the effects mediated by HGF in vitro. The mutant embryos do not reveal any obvious delay or defect in the convergence of spinal nerves to form the brachial plexus17, 18. However, axons emerging from the plexus to form distinct limb nerves show a significant reduction in length. Interestingly, certain nerves appear more affected than others. High levels of met expression are restricted to subsets of motor neurons in the parts of the spinal cord that innervate the limbs, suggesting that the affected axons may correspond to muscle-specific pools of Met-positive motor neurons, which beyond the plexus are confined to particular nerve branches. Both the sites of Met expression and the defects observed in hgf and met mutant mice are consistent with the simple explanation suggested by in vitro data, namely that HGF from mesenchyme serves to guide specific populations of Met-expressing axons toward their targets. However, motor neurons also depend on trophic factors secreted by muscle, and HGF is required for muscle development, leaving open the possibility that some of the observed defects in vivo arise as a secondary consequence of the lack of muscles.

HGF promotes motor neuron survival
In addition to its role as a chemoattractant, HGF can also induce the survival of a subpopulation of motor neurons during development. In cultures of purified embryonic rat motor neurons, HGF promotes short-term survival, with an efficiency comparable to that of other neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF)17, 19, 20. Consistent with the pattern of Met expression in vivo, motor neurons from limb-innervating brachial segments show a more potent survival response to HGF than do thoracic motor neurons20. Thus HGF secreted by limb mesenchyme could selectively support the survival of motor neurons in the limb-innervating segment. HGF and CNTF seem to act in synergy, because a combination of the two factors can rescue neurons that are not rescued by saturating concentrations of either factor alone19 ( Fig. 1). This is consistent with the emerging view that most motor neurons can respond to multiple factors from diverse sources for their optimal survival21. CNTF may potentiate the response to HGF of those motor neurons that express subthreshold levels of Met, which are insufficient to elicit a response to HGF alone. The peaks of HGF expression in the limb, and of Met expression in motor neurons, both coincide with the period of naturally occurring cell death10, 17, 20, and the expression of Met in motor neurons is later downregulated. Motor neurons may thus require distinct factors at different stages of their development. HGF could regulate or enhance motor neuron survival in a precise developmental window, before motor neurons switch their dependency towards other factors secreted by their future muscle targets. These muscle-derived factors, rather than HGF, would be responsible for matching the number of surviving motor neurons to the size of their target. A similar process may also operate in other neuron types, such as sensory and sympathetic neurons.

Figure 1. Summary of HGF effects on motor neurons, sensory neurons and sympathetic neurons.
Figure 1 thumbnail

The figure describes distinct biological functions of HGF at different time points during neurogenesis. Open spaces indicate lack of data. The words 'induced' and 'promoted' are used when HGF acts alone; 'enhanced' indicates cooperation with another factor. The reduction in axonal outgrowth of motor nerve branches described in the hgf/met mutants could be a direct defect or a consequence of the lack of muscle (see text for details).



Full FigureFull Figure and legend (23K)
HGF enhances the effects of NGF on sensory neurons
During embryogenesis, the HGF/Met system is also required for development of the sensory neurons of the dorsal root ganglia (DRG). Although HGF alone does not promote neurite outgrowth in DRG explants, it markedly enhances the outgrowth that occurs in response to NGF. This observation was confirmed using cultures of dissociated sensory neurons, in which HGF is able to enhance many of the effects of NGF, including the maturation of sensory neuron progenitors, as well as the survival and the axonal growth rate of these neurons18 (Fig. 1). Moreover, mutant embryos lacking Met show increased numbers of apoptotic cells in the DRG, as well as a reduction in the network of sensory fibers innervating the skin of the limbs and thorax18. Thus, the in-vitro effects of HGF and the defects in the met mutant embryos both point towards a specific requirement of HGF and Met in DRG neurons. The level of Met expression in these neurons (as in sympathetic neurons) is, however, very low; the protein can be detected using anti-Met antibody staining, but the level of Met mRNA is so low as to be almost undetectable by in situ hybridization. This low level of Met expression might explain why HGF cannot act alone in these cells but can only potentiate the effects of NGF, whereas in other cell types it is able to induce biological responses by itself. The synergy with NGF seems to be relatively specific; even though Met is also expressed in other populations of DRG neurons that depend on BDNF and NT3 rather than NGF for their survival, HGF does not enhance responses to these neurotrophins. Similar results have been found with cranial sensory neurons from the trigeminal and nodose ganglia, in which the effects of BDNF and NT3 are not enhanced by HGF (A.M. Davies, personal communication). Such specificity could be due to differences in signaling between the different neurotrophin receptors (see below).

HGF has autocrine effects on sympathetic neuroblasts
Sympathetic neurons show a remarkable range of responses to HGF at different stages of development. Sympathetic ganglia are neural-crest-derived structures in which proliferating neuroblasts mature into postmitotic sympathetic neurons; these neurons express the NGF receptor TrkA and become dependent on NGF (and to a lesser extend on NT3) for their survival and axonal outgrowth22, 23. In early sympathetic ganglia, HGF seems to be produced by the neuroblasts themselves, suggesting that HGF acts in an autocrine or local paracrine mode24. Experiments in which the fate of single cells is followed over time in culture demonstrate that endogenously produced HGF enhances the survival and differentiation, but not the proliferation, of sympathetic neuroblasts24 (Fig. 1). Consistent with these in-vitro effects, sympathetic ganglia of met mutant mice show an approximately twofold increase in apoptotic cells, and a progressive reduction in the total number of cells24.

As with sensory neurons, HGF cooperates with NGF to enhance sympathetic neuron axonal outgrowth, and also to increase the numbers of neurites emerging from the cell bodies24 (Fig. 1). In contrast to sensory neurons, however, HGF fails to cooperate with NGF in promoting the survival of postmitotic sympathetic neurons, suggesting that in sympathetic cells Met activates the survival pathways only weakly, if at all24, 25.

HGF secreted by neurites locally activates Met on axons, thereby enhancing axonal outgrowth25. This has been shown by plating sympathetic neurons into compartmented dishes, with the cell bodies and proximal neurites located in a separate compartment from the distal neurites. When neutralizing anti-HGF antibodies were added to the compartment containing distal neurites, the rate of axonal growth was decreased, indicating that HGF acts locally to enhance the axonal growth rate25. Sympathetic axons can still respond to exogenous HGF under these conditions, suggesting that local endogenous release of HGF is not sufficient to saturate the receptors24, 25. Whether each individual axon stimulates its own growth or whether HGF signals between multiple growing axons remains unclear. Either way, local effects of this type could be important in vivo, both during normal development before axons have contacted their targets, and during nerve regeneration. The emerging idea is that axonal growth before contact with the target resembles axonal regeneration, and that both processes are distinct from the later process of target innervation and reinnervation. HGF signaling among axons may be important in the earlier stage, and may serve to amplify responses to low levels of neurotrophins.

Neurogenic effects and signaling mediated by Met
When it is bound by HGF, the Met receptor activates cytoplasmic effectors through a multifunctional docking site located in its carboxy-terminal tail26. In nonneuronal cells, Met can activate several signaling cascades, including the Ras/MAP kinase and JNK/SAP kinase pathways via Grb2 and Gab1, phospholipid pathways through binding of phosphatidylinositol-3 kinase (PI3K) and phospholipase Cgamma (PLCgamma), phosphotyrosine-mediated pathways through interaction with Src tyrosine kinase, SHP2 tyrosine phosphatase, Nck and the STAT pathway26, 27, 28, 29, 30, 31 ( Fig. 2). The multiple effects mediated by HGF in neurons raise the interesting question of whether these different effects are mediated by different intracellular signaling pathways. Although the survival effects mediated by Met probably involve the activation of Ras/MAPK and PI3K/Akt pathways, it is unclear which signaling cascades are responsible for differentiation, axonal outgrowth and chemoattraction. It would be interesting to know whether axonal outgrowth involves the same intracellular mechanisms as muscle precursor migration or tumor cell metastasis, given that all these processes involve the regulation of adhesion molecules. Adhesion molecules are known to be regulated by tyrosine phosphorylation, and recently HGF was shown to stimulate tyrosine phosphorylation of focal adhesion kinase (p125FAK), a cytoplasmic tyrosine kinase involved in integrin-mediated signal transduction32. In addition, outgrowing axons can secrete proteases33, 34, and Met has been implicated in the degradation of extracellular matrix by increasing the production of two proteases, collagenase and urokinase3, 35. Axonal outgrowth and navigation also involves cytoskeletal rearrangements, suggesting a possible analogy with the scattering activity of HGF. Epithelial cell scattering involves the activation of both PI3 kinase and the Ras-Rac/Rho pathways36, 37, 38, 39, both of which are known to regulate the cytoskeleton.

Figure 2. Schematic representation of signaling pathways activated by HGF, and potential synergistic actions with CNTF and NGF.
Figure 2 thumbnail

HGF binds and activates a series of signaling proteins that may be differentially involved in distinct biological responses. The survival effect mediated by Met may involve the activation of Ras and PI3 kinase, which are also activated by NGF and CNTF. Thus the cooperation between HGF and these neurotrophins may result from an enhancement of the kinetics of activation of these two pathways. Developing axons control motility of their growth cones by modulating both protease levels and cytoskeletal organization. Axonal outgrowth could resemble cell motility, which involves several pathways known to be activated by HGF. These include degradation of extracellular matrix by increased protease secretion, as well as activation of Ras, PI3 kinase, src and p125FAK. Other pathways activated by HGF/Met signaling include Nck, STAT3, JNK and PLCgamma.



Full FigureFull Figure and legend (36K)
Using a signaling mutant in which the Grb2 adapter protein is uncoupled from the Met receptor (metgrb2/grb2), we have demonstrated in vivo that an intact Grb2 binding site on Met is required for limb muscle development and for secondary fiber formation in axial muscles9. In contrast, the actions of HGF on peripheral sensory neurons are not affected by mutating the Grb2 binding site, and so presumably are mediated by different downstream effectors18. By testing the effects of mutations in the Met receptor in mutant mice, it should be possible to uncover the signaling pathways by which HGF affects neuronal development and function.

As discussed above, HGF cooperates with CNTF to promote motor neuron survival19, and with NGF to promote sensory neuron survival and outgrowth of sensory and sympathetic axons18, 24, 25. These findings suggest that there must be a convergence among the downstream signaling pathways of Met and of the CNTF receptor and the NGF receptor (TrkA). Indeed, these receptors share some downstream effectors, including PI3 kinase, PLCgamma, STATs and the Ras/MAPK pathway (Fig. 2). One challenge for any model of signal convergence is to explain why even though Met seems to be expressed by all populations of DRG sensory neurons in culture, HGF synergizes only with NGF and not with the related neurotrophins BDNF or NT3 (18). The receptors for NGF, BDNF and NT3 (TrkA, TrkB and TrkC, respectively) are closely related, yet there presumably must be some mechanism by which only TrkA receptors can cooperate with Met. One attractive hypothesis is that HGF could be an enhancer of a signal specified by NGF. Alternatively HGF may activate a set of unique pathways, or block an inhibitory molecule that turns off pathways activated by NGF.

HGF and regeneration
The ability of neurotrophins to promote survival and axon regeneration in diverse neuronal systems has raised the possibility of pharmacological therapy for neurodegenerative disorders40, 41, 42. In many cases, however, the maintenance of neurons depends on many different neurotrophic factors acting in concert. Therefore, rather than using one factor alone, it may be beneficial to treat with combinations of neurotrophic factors that have complementary effects on neuron survival, regeneration and function43. In the last three years, NGF has been tested for the treatment of neurodegenerative diseases like Alzheimer's disease44, 45, and of peripheral neuropathies that can occur in diabetes and during anti-cancer therapy46, 47. HGF specifically enhances the neurotrophic activity of NGF in sympathetic and DRG sensory neurons, but it is not yet known whether this is also true for the effects of NGF on central neurons. Among the possible targets are the basal forebrain neurons, which degenerate during Alzheimer's disease and which, like motor neurons, are cholinergic and express Met. NGF prevents forebrain cholinergic neurons from becoming atrophic after axotomy, and it will be interesting to determine whether HGF can enhance this effect. HGF has already been proposed as a possible therapeutic agent for muscle and liver regeneration48, 49, 50; if it can cooperate with other neurotrophins, its therapeutic potential may be extended to the nervous system by allowing neurotrophins to be administered at lower doses with fewer side effects.

Conclusions
The complexity of defects in hgf and met mutant mice during the early stages of neuronal development, the pleiotropic functions of HGF/Met in other cell types, and the cooperation with other signaling molecules such as NGF and CNTF, all suggest that the main role of HGF is to enhance cellular survival, growth rate and migratory behavior. HGF does not seem to instruct neural precursors to commit to a specific cell lineage. Although it may have an instructive role in motor neurons—where it affects both axon guidance and cell survival—its role in most cell types seems to be to enhance their ability to respond to more specific signals, with the particular cell fates chosen depending upon the developmental history of each cell type and the specific signaling pathways operating within it. To the extent that HGF acts as an enhancer molecule, it may also be able to support the survival and regeneration of lesioned neurons. With these tools in hand, it should now be possible to test this hypothesis in animal models.

Received 29 October 1998; Accepted 27 January 1999

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Acknowledgments
We are grateful to F. Helmbacher for assistance with figures, and to F. Helmbacher, R. Dono, G. Wilkinson, and K. Kullander for comments on the manuscript. F.M. is supported by a grant from the DFG (SFB 317). Our own work is in part supported by an EU Biotechnology network grant.

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