Introduction—Fibroblast Growth Factors (FGFs) and FGF Receptors

The FGFs comprise a large group of structurally similar polypeptide mitogens which currently includes 22 different members. The first members of this family, FGF1 (acidic FGF, aFGF) and FGF2 (basic FGF, bFGF), were described in 1986 by Jaye et al¹ and Abraham et al.² In the meantime, 20 other FGFs have been discovered which were designated FGF3-FGF23. FGF19 has so far only been described in humans and FGF15 only in mice, and it has been suggested that FGF19 is the human ortholog of mouse FGF15. All members of the FGF family range in molecular weight from 17 to 34 kDa in vertebrates, and some of them are glycosylated (for review see ref. 3).

Most of the FGFs have a classical amino-terminal signal sequence and are, therefore, efficiently secreted via the endoplasmic reticulum-Golgi secretory pathway. FGF9, 16 and 20 lack an obvious amino-terminal signal peptide, but are nevertheless secreted. FGFs11–14 are thought to remain intracellular, and secretion of these FGFs has not yet been observed. Although FGF1 and FGF2 lack a signal sequence and are normally located in the cytoplasm or in the nucleus, they can be found on the cell surface and within the extracellular matrix. They are either released from damaged cells or secreted by an alternative exocytotic mechanism that bypasses the endoplasmic reticulum Golgi pathway(for review see refs. 3,4).

FGFs have been shown to interact with three different types of binding partners: heparan sulphate proteoglycans,^3–5 a cysteine-rich transmembrane FGFbinding protein which appears to be involved in the regulation of intracellular FGF trafficking,⁶ and four high-affinity transmembrane FGF receptors of the tyrosine kinase family which are responsible for signal transduction.⁷ The FGF receptors, FGFR1-FGFR4, are transmembrane protein tyrosine kinases with either two or three immunoglobulin-like domains and a heparin binding sequence in the extracellular part of the receptor. Alternative mRNA splicing generates receptors with different carboxyl-terminal halves of the third immunoglobulin-like domain, designated IIIb or IIIc isoforms. This alternative splicing event is regulated in a cell- and tissue-specific manner and has been shown to dramatically affect ligand-receptor binding specificity.⁷ The different members of the FGF family bind to the receptor splice variants with different affinities. Most FGFs bind to a specific subset of FGF receptors. FGF1, however, binds to all known receptors, and FGF7 specifically interacts with the IIIb isoform of FGFR2.⁸

A characteristic feature of FGFs is their interaction with heparin or heparan sulphate proteoglycans. These interactions stabilize FGFs and may limit their diffusion and release into interstitial spaces. Most importantly, the interaction of FGFs with heparin or heparan sulphate proteoglycans is essential for the activation of the signaling receptor.^3,5

Most members of the FGF family have a broad mitogenic spectrum. They stimulate proliferation of a variety of cells of mesodermal, ectodermal and also of endodermal origin.^3,4 The only known exception is FGF7, which seems to act only on epithelial cells, at least in the adult organism.⁹ FGFs are not only mitogenic, but they also have the capacity to regulate migration and differentiation in vitro and in vivo. Finally, some of the FGFs have been shown to be cytoprotective (see below).^3,9

FGFs and their receptors are expressed at multiple sites in the developing and adult animal, suggesting important roles of FGFs in development and tissue homeostasis. This hypothesis was confirmed by the wide variety of phenotypic abnormalities observed in FGF and FGFR knockout animals.³ Finally, abnormalities in FGF/FGF receptor signaling are associated with human disease, including cancer and various genetic disorders.

Distribution of FGFs in Adult Brain

The brain is a rich source of various FGFs. While the expression pattern of FGF2 has been studied in detail (for review, see refs. 10,11), data on the mRNA expression and the immunoreactivity of the other FGFs is relatively sparse. Both FGF1 and FGF2 have been localized to glial cells and neurons of the CNS. Notably, high levels of FGF1 were found in neurons of brain regions that are at high risk for neurodegenerative diseases such as Alzheimer's disease (magnocellular forebrain cholinergic neurons), Parkinson's disease (substantia nigra neurons) and amyotrophic lateral sclerosis (motor neurons).¹¹ Most, if not all astrocytes of the brain express Fgf2, whereas a prominent neuronal localization appears to be confined mainly to neurons in the CA2 region of the hippocampus.¹² In both astrocytes and CA2 neurons, Fgf2 immunoreactivity is localized primarily in the nucleus and to a lesser extent in the cytoplasm and the processes of stained cells.¹³ Fgf5 mRNA is widely distributed at low levels in the brain, with several loci of Fgf5 expression found in the cerebral cortex, hippocampus and thalamus. At least some of the Fgf5 expressing cells appear to be neurons.¹⁴ Fgf7 mRNA could not be detected in any of the postnatal brain regions examined so far.^15,16Fgf9 mRNA is moderately to weakly expressed in widespread regions of the brain, with some preference to brain regions involved in motor control (red nucleus, parts of cerebellum, oculomotor nucleus). The cellular localization of Fgf9 mRNA indicated that this FGF family member is mainly produced by neurons.^17,18 Expression of the Fgf10 gene is spatially restricted to some regions of the brain, including hippocampus, thalamus, and several nuclei in midbrain and brainstem, with a pre-ferential expression in neurons rather than in glial cells.¹⁵ Interestingly, with its predominant expression in the CA1 and CA3, but not in the CA2 region of the hippocampus, the spatial distribution of Fgf10 mRNA is just opposite to that of Fgf2 mRNA, which is largely confined to the CA2 region, suggesting that the two FGFs have distinct functions in the hippocampus. Finally, Fgf14 mRNA was recently detected in the brain, with FGF1–41b as the predominant isoform. The developmental expression pattern suggests that FGF14 plays a significant role in cerebellar development.¹⁹

All FGF receptors are expressed in the brain. The Fgfr1 gene is significantly expressed in select neuronal populations, but also in astrocytes and oligodendrocytes.^20,21 FGFR2 and FGFR3 are predominantly found in astrocytes and oligodendrocytes,^22,23 whereas FGFR4 is almost exclusively expressed in neurons of the medial habenular nucleus.²⁴

FGFs and Neuronal Development

FGFs and their receptors (FGFRs) have been implicated in many aspects of neuronal development, where they promote proliferation, differentiation and axonal branching. For example, FGF8 regulates growth and patterning of the midbrain and the anterior forebrain,^25,26 FGF3 plays an essential role in the development of the inner ear,²⁷ and FGF8, FGF14, FGF15, FGF17, and FGF18 are expressed in the developing cerebellum.^19,28 Demonstrating the significance of FGFs for appropriate cerebellar development, a phenotype displaying gait defects was observed in FGF17^−/− and FGF8^Δ2,3n/+ mice, albeit with low penetrance.²⁸ FGF2 appears to be intimately involved in cortical development (for review see refs. ^29,30). It supports the survival of neurons from many regions of the fetal rat brain, including hippocampus, cortex, thalamus and striatum.^31,32 In addition to its neurotrophic effects, FGF2 acts as a mitogenic factor, stimulating the proliferation of neuronal progenitor cells. Most interestingly in the context of this chapter, FGF2 is capable of activating a latent neurogenic program in neural stem cells from diverse regions of the adult brain and of stimulating neurogenesis in the mature CNS.^33–35 FGF2 is present in the telencephalon as early as E9.5 and high levels are found in the cerebral cortex throughout neurogenesis and into adulthood.¹⁰ FGF2 appears to exert a dual function on early phases of cortical neuroectoderm cell proliferation and later phases of differentiation. Since astrocytes appear to be the predominant source of FGF2, with only few neuronal populations displaying FGF2 immunoreactivity (see above), glial cells might provide trophic support to neuronal cells.¹² Despite accumulating evidence from in vitro studies, which strongly implicate FGF2 as a neurotrophic factor, it was not before the generation of mice lacking FGF2 that the issue of whether endogenous FGF2 is essential for survival of cortical neurons was settled. Neurohistological analysis of FGF2 knockout mice revealed abnormalities in the cytoarchitecture of the neocortex, combined with a significant reduction in neuronal density, most pronounced in layer V.^36,37 It was concluded that one important role of FGF2 during cortical neurogenesis may be to amplify the progenitor pool for pyramidal projection neurons.³⁸ Data from several developmental studies indicate that FGF2 also acts as a target-derived factor that promotes axon branching of cortical neurons. Specifically, FGF2 may induce the formation of collateral axon branches by its effects on the morphology and the behavior of the primary growth cone.³⁹ The strong effect of FGF2 on neurite morphogenesis has been linked to the increase by FGF2 of L-type Ca²⁺ channels in fetal neurons.⁴⁰

Upregulation of FGFs after Brain Injury

The expression of many neurotrophic factors in CNS neurons is regulated by physiological stimuli, such as afferent synaptic activity, suggesting that these factors participate in functional and/or morphological changes associated with neuronal plasticity. More dramatic alterations in the expression pattern of many neurotrophic factors are induced by several forms of acute brain injury.⁴¹ Since the late 1980's, numerous publications have accumulated evidence for a pronounced upregulation of FGFs in the cellular response to acute brain injury. Among the FGF family members, FGF2 clearly emerged as the central player in acute CNS damage, and we will hence focus the following section on this factor. FGF2 upregulation was demonstrated after mechanical brain injury,^42–48 after ischemic insults,^49,50 and after convulsive seizures.^51–54 Three days after of mechanical cortical injury, macrophages are the predominant FGF2 immunoreactive cells at the lesion site. A second phase of increased FGF2 expression, which peaks at about one week post-lesion, is mediated by activated astrocytes and microglia, particularly at the border between the neuronal and scar tissue. Although multiple cells within the lesioned CNS, including astrocytes, microglia, neurons and vascular endothelial cells, might all be able to express FGF2, glial cells appear to be the primary source of the newly synthesized FGF2. In support of this notion, the gradual fall in FGF2 levels one week after injury parallels the concomitant decrease in reactive glia.⁴⁵ Interestingly, an increase in the intensity of FGF2 immunoreactivity was also detected within the extracellular matrix surrounding the lesion, suggesting that FGF2 was released from astrocytes and becomes available to neurons.⁴⁶ A similar time course of induction of glial FGF2 synthesis was observed after transient forebrain ischemia.⁴⁹ In contrast to the slow, but sustained upregulation of FGF2 in traumatic or ischemic lesion models, a faster and transient response was induced by epileptic convulsions not associated with neuronal loss. For example, seizures induced by microinjection of the GABA_A receptor antagonist, bicuculline, in the deep prepiriform cortex lead to a significant increase in FGF2 mRNA in the entorhinal cortex, the hippocampus and the olfactory bulb within 5 hours of epileptic activity.⁵¹ However, if seizure activity was severe enough to produce neuronal loss and reactive astrocytosis, a long-term induction of FGF2 gene expression for up to 2 weeks was observed in the damaged region.⁵³ Although astrocytes appear to represent the main source of FGF2 in seizure models, elevated FGF2 mRNA signals were also observed in select neuronal populations.^54,55

Upregulation of FGF2 also has been implicated in the protective effect of cortical spreading depression (SD) against subsequent ischemic damage.^56,57 Cortical SD is a rapid and nearly complete, but reversible depolarization of a large population of neurons, which propagates in a slow wave-like fashion through the gray matter (for review see ref. 58 and Chapter 5 of this book). The protective effect of SD against ischemic insults might last for several days suggesting that some kind of sustained downmodulation of neuronal vulnerability is initiated. Right now, it is not clear whether the upregulation by SD of FGF2 is a pivotal mechanism affording enhanced protection against subsequent stroke. However, with the generation of FGF2 deficient mice (see above), this intriguing issue should be resolved in the near future.

Neuroprotective Effects of FGF2

Among the various growth factors and cytokines studied so far, the neuroprotective and neurotrophic profile of FGF2 is best documented (reviewed in ref. 59). If administered during or within hours of acute injury, systemic or intracerebroventricular (icv.) FGF2 reduces infarct size after stroke,^60–66 diminishes histopathologic damage associated with fluid percussion injury,⁶⁷ affords neuroprotection against N-methyl-D-aspartate (NMDA) and kainate receptor-mediated excitotoxicity, ^60,68,69 and prevents the death of axotomized CNS neurons.^70–74 It is worth noting that FGF2, which is highly neuroprotective against seizure-induced long-term behavioral deficits, might also act as a convulsant at higher concentrations.⁷⁵ If administered 1 day after focal cerebral infarction, intracisternal FGF2, although no longer reducing infarct size, is still capable of enhancing behavioral recovery.⁷⁶ Correspondingly, blockade of FGF2 by neutralizing antibodies retarded recovery of forelimb manipulatory abilities after unilateral suction lesion of the motor cortex.⁷⁷ Further support for a beneficial role of FGF2 in acute brain injury comes from a study in which mice expressing a bovine FGF2 transgene in the brain showed increased resistance to hypoxemic-ischemic cerebral damage.⁷⁸ The finding that intravenous FGF2 rapidly crosses the blood brain barrier in adult brain, with the levels in blood plasma and cerebrospinal fluid rising in parallel, bears particular significance for the application of this factor in a clinical setting.^34,78A As a result of the outstanding benefits of FGF2 in various animal lesion models and its high cerebral bioavailability after intravenous injection, clinical trials of intravenous FGF2 (Fiblast) in acute stroke were conducted. In a North American phase II/III trial, 302 patients suffering from acute ischemic stroke were enrolled between August 1997 and May 1998, when enrollment was halted by the Data Safety Monitoring Committee following an interim analysis, which revealed an unfavorable risk-to-benefit ratio in stroke patients treated with FGF2 versus those treated with placebo (information according to the Internet Stroke Center at www.strokecenter.org).

Data on the possible neuroprotective potential of other FGFs is sparse. Several studies found beneficial effects of FGF1 (acidic FGF) in animal models of acute ischemic or excitotoxic brain damage.^79–83 A recent study demonstrated that FGF7 (keratinocyte growth factor) prevents ischemia-induced delayed neuronal death in the hippocampal CA1 region of the gerbil brain.⁸⁴ Finally, FGF8 was shown to protect cultured hippocampal neurons from oxidative insult.⁸⁵

FGFs and Glia

Given that FGF2 is mitogenic for oligodendrocytes and astrocytes and stimulates migration and functional differentiation of astrocytes, one might wonder whether, in addition to its neuroprotective effects, FGF2 may also have the undesirable side effect of promoting scar formation (for review see ref. 86 and Chapter 4 of this book). Although the involvement of FGF2 in scar formation appears minor compared to that of other potent fibrotic agents such as TGF-β₁, several reports lend credence to the notion that FGF2 is not an innocent player in the glial response to acute brain injury. For example, the reactive gliosis following mechanical or electrolytic lesions in the neonatal and adult brain was significantly augmented and accelerated by FGF2 injected into the lesion site just after the lesion was performed.^87–89 Along the same lines, FGF2, if injected into various regions of the noninjured adult rat brain, produced a glial reaction that resembled the reactive gliosis seen after brain injury.⁸⁹ Supporting its involvement in extracellular matrix remodeling after injury, FGF2 was found to increase the production of tenascin-C mRNA and protein in cultured hippocampal astrocytes.⁹⁰ It should be pointed out, however, that the effects of FGF2 on glial cells might also indirectly promote survival of select neuronal populations, as FGF2 (and FGF1) were found to stimulate nerve growth factor (NGF) synthesis and secretion by astrocytes.⁹¹ Since intercellular communication between astrocytes through gap junctions is essential to many of their functions, the finding that FGF2, FGF5 and FGF9 downregulate astroglial gap junctions and functional coupling in a brain region-specific fashion is of particular interest.⁹² It is well documented that acute brain injury is associated with downregulation of connexin 43, the predominant component of astroglial gap junctions. One might thus speculate whether the lesion-induced upregulation of FGFs causally linked to the uncoupling of astrocytes.

Neuroprotective Mechanisms of FGF2

Interaction Between FGF2 and Activin A

In a collaborative study between our laboratories, we made the intriguing observation that induction of activin A, a member of the transforming growth factor-β (TGF-β) superfamily (see next chapter), is essential for the neuroprotective action of FGF2 in vivo.¹¹² Like the other members of the TGF-β superfamily, activins are dimeric proteins, consisting of two β_A subunits (activin A), two b_B subunits (activin B) or a β_A and a β_B subunit (activin AB). In addition, β_C, β_D, and β_E subunits have been identified, although the corresponding proteins have not been characterized in detail. The β_A and β_B subunits can also dimerize with a homologous a subunit, leading to the formation of inhibin A (αβ_A) or inhibin B (αβ_B). Previous findings from our and other laboratories already pointed to a possible involvement of activin A in the early neuronal response to injury (Fig. 1C).^113–117 Since activin A promotes survival of midbrain and hippocampal neurons in vitro,^118,119 reduces ischemic brain injury in infant rats,¹²⁰ and protects striatal and midbrain neurons against neurotoxic damage,^118,121 we speculated that the lesion-induced upregulation of activin A might serve an excitoprotective function. A first indication for a possible interaction between FGF2 and activin A came from a comparison between the activin β_A mRNA expression pattern in lesioned and in FGF2-protected hippocampi. In our lesion model, exogenous FGF2 abolished the neuronal damage in the CA3 region of the ipsilateral hippocampus which is typically seen after intracerebroventricular (icv.) application of this excitotoxin (Fig. 1A). Unexpectedly, FGF2 also produced a strikingly stronger upregulation of β_A mRNA than KA injection alone (Fig. 1B). FGF2 substantially augmented β_A mRNA expression on the ipsilateral side at 6h and 24h postlesion, without appreciably influencing the time course of signal elevation. Two independent sets of experiments corroborated the hypothesis that activin A is crucially involved in the neuroprotective effects ascribed to FGF2. First, recombinant activin A was as effective as exogenous FGF2 in preventing excitotoxic neuronal loss (Fig. 1E). Second, the activin-binding protein follistatin, which neutralizes activin in vitro and in vivo,^122,123 consistently abrogated the beneficial action of FGF2 in the KA lesion model (Fig. 1F). Control experiments dispelled concerns that follistatin caused neuronal damage by a mechanism other than its activin-neutralizing action. A different type of interaction between FGF2 and the TGF-β superfamily was reported from cultured midbrain dopaminergic neurons, in which the neurotrophic effect of bFGF was mediated by TGF-β1–3.¹²⁴ In contrast to activin A, which is of neuronal origin in lesioned hippocampus, the effect of the TGF-βs was mediated by cocultured glial cells.

Figure 1

Induction of activin A is an essential step for the neuroprotective action of FGF2 (bFGF) in an animal model of select excitotoxic neuronal loss. A: Intracerebroventricular (icv.) injection of FGF2 prevents the loss of hippocampal CA3 neurons (lower micrograph), (more...)

The main neuroprotective mechanisms of FGF2 are summarized in Fig. 2. As it is becoming evident that induction of activin A is an essential step in the signaling cascade affording neuroprotection after application of FGF2, it remains to be determined which of the effects, originally attributed to FGF2, are directly mediated by this growth factor, and which require upregulation of activin A.

Figure 2

Synopsis of neuroprotective signaling pathways influenced by FGF2. (−) and (+) indicate attenuation and enhancement, respectively, of respective target by FGF2. Induction by FGF2 of activin A plays a central role, but it remains to determined (more...)

Summary and Conclusions

Several members of the FGF family, in particular FGF2, are intimately involved in neuronal protection and repair after ischemic, metabolic or traumatic brain injury. Expression of Fgf2 mRNA and protein is strongly upregulated after neuronal damage, with glial cells as the predominant source. Given its survival-promoting effects on cultured neurons, exogenous FGF2 was tested in several animal models of stroke and excitotoxic damage, in which it consistently proved protective against neuronal loss. FGF2 affords neuroprotection by interfering with a number of signaling pathways, including expression and gating of NMDA receptors, maintenance of Ca²⁺ homeostasis and regulation of ROS detoxifying enzymes. FGF2 prevents apoptosis by strengthening antiapoptotic pathways and promotes neurogenesis in adult hippocampus after injury. The protective action of FGF2 has been linked to its augmenting effect on the lesioninduced upregulation of activin A, a member of the TGF-β superfamily. Despite the well-documented benefits of FGF2 in animal models of stroke, there is currently no clinical development in stroke, after a phase II/III trial with FGF2 in acute stroke patients was discontinued because of an unfavorable risk-to-benefit ratio. As the molecular targets of FGF2 are going to be unraveled over the next years, new therapeutic strategies will hopefully emerge that enable us to influence the various protective mechanisms of FGF2 in a more specific fashion.

Acknowledgments

The authors thank David Ornitz for comments on the manuscript. The work of the authors was supported by the Deutsche Forschungsgemeinschaft (DFG), the Bundesministerium für Bildung und Forschung (Bmb+f), and the Human Frontier Science Program.

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