Download Fibroblast growth factors as regulators of central nervous system

Am J Physiol Regul Integr Comp Physiol 284: R867–R881, 2003;
10.1152/ajpregu.00533.2002.
invited review
Fibroblast growth factors as regulators of central
nervous system development and function
Rosanna Dono
Faculty of Biology, Department of Developmental Biology, Utrecht University,
NL-3584CH Utrecht, The Netherlands
neural stem cells; anterior neural ridge; isthimic organizer; neocortex;
neural development
FIBROBLAST GROWTH FACTORS (FGFs) constitute a large
family of structurally related polypeptide growth factors found in organisms ranging from nematodes to
humans (17, 53, 71, 74, 148, 189, 200). To date, the
mammalian FGF proteins are encoded by twenty-two
distinct genes known as Fgf1 to Fgf18 and Fgf20 to
Fgf23 in the mouse (25, 71, 133, 189, 236). FGF proteins are small peptides of 155 to 268 amino acid
residues (25, 71, 148, 189, 235). The degree of sequence
identity between different family members is 30–60%
in a “central domain” of ⬃120 amino acids. This domain confers to FGFs a common tertiary structure and
the ability to bind to heparin (42, 245). Most FGFs are
constitutively secreted using the endoplasmic reticulum-Golgi secretory pathway (77, 89, 203, 235). A small
subgroup of FGF proteins, such as FGF1, -2, -9, -16,
and -20, lacks the NH2-terminal signal sequence but is
still transported in the extracellular space (36, 103,
135, 137). A third subgroup of FGF proteins, FGF11 to
FGF14, lacks the signal peptide and remains intracellular (182).
Secreted FGFs signal to target cells by binding and
activating cell-surface tyrosine kinase FGF receptors
(FGFRs; 34, 82, 105, 146). FGFRs are transcribed from
four different genes and consist of an extracellular
domain, a single transmembrane domain, and a cytoplasmic tyrosine kinase domain (34, 82, 105). The extracellular domain contains three immunoglobulin-like
Address for reprint requests and other correspondence: R. Dono,
Dept. of Developmental Biology, Faculty of Biology, Utrecht Univ.,
Padualaan 8, NL-3584CH Utrecht, The Netherlands (E-mail:
[email protected]).
http://www.ajpregu.org
domains, called loops I, II, and III (81, 105). Although
loops II and III contact the bound ligand, the region
that dictates the specificity of binding is the COOHterminal portion of loop III (20, 150). Alternative
mRNA splicing of the COOH-terminal portion of loop
III creates several forms of FGFRs with unique ligandbinding properties (81, 150, 212). Once an FGF ligand
is bound, the receptor dimerizes and phosphorylates
intermolecular tyrosine residues, triggering initiation
of FGFR signal transduction (97, 138, 159). FGFR
signaling activates a number of signal transduction
molecules, including those of the Ras and phospholipase C-␥ pathways (92, 97, 139, 221). Interestingly,
the intracellular FGF12 and FGF14 do not bind to
FGFRs; nevertheless, they interact with the mitogenactivated protein (MAP) kinase scaffold protein IsletBrain-2 in neurons (145, 182, 222). The regulation of
FGFR-ligand interaction is complex. Receptor isoforms
can form heterodimers and share redundant ligand
binding specificity (150). Moreover, ligand binding is
affected by the distribution of heparan sulfate proteoglycans (HSPGs) on the cell surface and in the extracellular matrix (109, 151, 190). Extracellular FGFs,
indeed, bind tightly to HSPGs, which may restrict FGF
diffusion and favor interaction with receptors on
nearby cells (11, 142). Finally, HSPGs promote and
stabilize assembly of the FGF ligand-receptor complex
(181).
The function of FGFs and FGFRs during embryonic
development and adult physiology has been addressed
by gain- and loss-of-function experiments in several
animal model organisms. These studies have shown
that FGFs act as key regulators of developmental
0363-6119/03 $5.00 Copyright © 2003 the American Physiological Society
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Dono, Rosanna. Fibroblast growth factors as regulators of central
nervous system development and function. Am J Physiol Regul Integr
Comp Physiol 284: R867–R881, 2003; 10.1152/ajpregu.00533.2002.—
Fibroblast growth factors (FGFs) are multifunctional signaling proteins
that regulate developmental processes and adult physiology. Over the
last few years, important progress has been made in understanding the
function of FGFs in the embryonic and adult central nervous system. In
this review, I will first discuss studies showing that FGF signaling is
already required during formation of the neural plate. Next, I will
describe how FGF signaling centers control growth and patterning of
specific brain structures. Finally, I will focus on the function of FGF
signaling in the adult brain and in regulating maintenance and repair of
damaged neural tissues.
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INVITED REVIEW
neural induction occurs via inhibiting BMP signaling
in prospective neural cells, since BMP signaling promotes epidermal cell fate (231). Fgf ligands and receptors are expressed by the prospective neural cells and
by the adjacent inducing tissues [Fgf2, -3, -4, and -8
(175, 194, 195, 232); FgfR1, FgfR2, and FGF3 (219,
232)]. The involvement of FGF signaling in this process
has been the subject of intense investigation since the
discovery that FGFs promote expression of neuronal
markers in Xenopus laevis ectodermal cells from an
early gastrula stage (87, 88, 101). It has been proposed
that FGFs are required for neural induction, since
inhibition of FGF signaling in Xenopus embryos interferes with development of neural tissue (73, 102).
Moreover, FGF2- and FGF4-soaked beads can induce
ectopic neural structures when applied to chick primitive streak stage embryos (5).
Dorsal ectodermal cells of an early Xenopus gastrula
acquire neural fates in response to signaling by Spemann organizer cells (230). These signals antagonize
BMP activity and thereby prevent specification of epidermal cell fates (100, 180). Known organizer signals
include the two BMP antagonists noggin and chordin
(163, 179, 247). Strikingly, inhibition of FGF signaling
in ectodermal explants from a Xenopus early gastrula
precludes the induction of neural tissues by the Spemann’s organizer (73, 102). Moreover, noggin- and
chordin-mediated neural induction is abolished in the
absence of FGF signaling (102, 179). Taken together,
these studies indicate that FGFs cooperate with BMP
antagonists to induce neural cell fates.
In apparent controversy, other studies in mouse and
chicken embryos have shown that in these vertebrates
BMP antagonists are not required for neural induction
FGFS DURING INDUCTION AND EARLY PATTERNING
OF THE NEURAL PLATE
Neural induction is the first and fundamental step in
the formation of the vertebrate CNS. During this process, pluripotent dorsal ectodermal cells undergo a “cell
fate switch” and become neural stem cells instead of
epidermal cell types (230). It is generally accepted that
Table 1. Fgfs and FgfRs in the developing CNS
Expressing Structure
Genes
Te
Di
Ms
Mt
My
Sc
Fgf1
Fgf2
●
●
●
●
●
●
●
●
●
●
Fgf3
Fgf7
Fgf8
●
●
●
Fgf9
Fgf10
Fgf11
Fgf12
Fgf13
Fgf14
Fgf15
Fgf17
Fgf18
FgfR1
FgfR2
FgfR3
FgfR4
ANR
●
AM
●
Is
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Phenotype
None
Neocortex, spinal
cord
Inner ear
None
Forebrain midbrain,
cerebellum
ND
ND
ND
ND
ND
None
ND
Cerebellum
ND
Early lethal, spina
bifida
Early lethal
None
ND
Ref. Nos.
2, 136, 227
36, 37, 153, 192
122, 229
126, 236
25, 134
23
Unpublished observation
189
68, 189
68, 189
222, 223
49, 133
235, 236
75, 236
152, 237, 239, 240
7, 37, 160
32, 158, 234
155, 224
Summary of expression in rat and mouse embryos. Phenotypes data derived from gene targeting experiments in mice. Fgf, fibroblast
growth factor gene; FgfR, fibroblast growth factor receptor gene; ANR, anterior neural ridge; AM, anterior midline; Is, isthmus; Te,
telencephalon; Di, diencephalons; Ms, mesencephalon; Mt, metencephalon; My, myelencephalon; Sc, spinal cord, ND, not determined.
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events. For example, FGFs control growth and survival
of the postimplantation mouse embryos (7, 43), cell
migration during gastrulation (21, 22, 199), and establishment of the anterior-posterior (A/P) body axis (22,
134). At later developmental stages, FGFs function in
those organs and tissues in which reciprocal interactions between epithelial and mesenchymal cells are
important for morphogenesis and differentiation (31,
183, 198). The discovery that certain human skeletal
disorders are caused by point mutations in FgfR1,
FgfR2, and FgfR3 (143, 149, 176, 228), and the genetic
analysis of FGFR and FGF ligand functions in the
mouse (23, 64, 112), have revealed essential roles for
FGF signaling in chondrogenesis and osteogenesis.
Disruption of FGF signaling may also underlie other
pathologies, such as hypotension (37, 244), diabetes
(67), and the hypophosphatemic rickets disorder (226).
In this review, I will focus on the function of FGF
family members in the central nervous system (CNS).
Several Fgfs and FgfRs are expressed in the embryonic
and adult CNS (Table 1 and Refs. 51, 69, 70, 189, 193,
233, 241). I will summarize some of the findings showing that FGFs act as key regulators of CNS development and function. I will also discuss studies that
address FGF signaling in the adult brain and neural
stem cells.
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Fig. 1. Schematic representation of the developing central nervous
system (CNS) in mouse embryos. A: sagittal view of a mouse CNS at
embryonic day 13. At this developmental stage, the embryonic neural
tube is already patterned along the anterior/posterior (A/P) and
dorso/ventral (D/V) axis. B: sagittal view of a postnatal day 2 mouse
brain. The progenitor cells of the neocortex are located in the ventricular (VZ) and subventricular (VZ) zone. Te, telencephalon; Di,
diencephalon; Ms, mesencephalon; Is, isthmus; R1 to R8, rhombomere 1 to rhombomere 8; SC, spinal cord; Nx, neocortex; Hp,
hippocampus; St, striatum; Th, thalamus; Cb, cerebellum.
FGFS AS MEDIATORS OF NEUROEPITHELIAL
ORGANIZER FUNCTIONS
Before neural tube closure, the developing CNS is
subdivided along its A/P axis, also known as the rostrocaudal axis, into the following four distinct domains:
the forebrain, the midbrain, the hindbrain, and the
spinal cord (246). At later developmental stages, the
forebrain gives rise to the anterior telencephalon and
the more caudal diencephalon (Fig. 1A and Ref. 246).
The midbrain will develop as one mesencephalic vesicle (Fig. 1A), whereas the hindbrain is divided in rhombomeres, with the most anterior rhombomere 1 and
rhombomere 2, known as the metencephalon (Fig. 1A).
As a result of these initial patterning events, the neural tube becomes regionalized, and neural progenitors
acquire positional identity. For example, spinal cord
progenitor cells will from now on generate spinal cord
neurons, whereas telencephalic progenitors will only
generate telencephalic neurons. It has been shown that
A/P patterning of the early neuroectoderm is controlled
by local signaling centers. These signaling centers act
within the neural plate to induce and maintain regional identity in the surrounding neuroepithelium.
For example, the anterior neural ridge (ANR), which
lies at the junction between the anterior ectoderm and
the anterior neural plate, is necessary for growth and
maintenance of the forebrain identity (188). The isAJP-Regul Integr Comp Physiol • VOL
thimic organizer (IsO) lies at the midhindbrain junction and regulates proper development of the mesencephalic and metencephalic derivatives [e.g., optic
tectum and cerebellum (124)]. FGF family members,
such as Fgf8, Fgf17, and Fgf18, are expressed at the
ANR and IsO (Fig. 2A and Refs. 25, 125, 235, 236).
Genetic and embryological studies have shown that
they play important roles in executing neuroepithelium organizer functions (188). For example, removal
of the ANR in neural plate explants leads to downregulation of Bf1 expression, a transcription factor essential for growth and patterning of the telencephalic
vesicles (188, 238). The fact that beads soaked with
FGF8 can induce Bf1 expression suggests that FGF8
can substitute for ANR functions (188). In agreement
with these studies, Fgf8 is expressed by the ANR cells
from day 8.5 onward (25), and embryos carrying a
hypomorphic Fgf8 allele have small telencephalic vesicles (134). Moreover, zebrafish embryos lacking a functional FGF8 protein (“acerebellar” mutants) show disruption of the commissural axon pathway and
patterning defects in the basal telencephalon (185).
The phenotypes observed in acerebellar mutants are
less severe than those resulting from ANR ablation
(185, 188) suggesting that FGF8 is not the only medi284 • APRIL 2003 •
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(10, 195, 196). Induction of the neural tissue occurs at
blastula stage and precedes establishment of a functional organizer [the mouse node and the chick Hensen’s node (91, 195, 232)]. In chicken embryos, FGF
signaling downregulates BMP expression in the prospective neural cells during blastula stages (232).
Streit et al. (195) have also shown that FGFs, produced
by organizer precursor cells at the posterior margin,
can initiate and promote neural tissue development
through a BMP-independent mechanism. Therefore,
FGF-mediated neural induction occurs via two distinct
mechanisms in chick epiblastic cells: the first mediated
by repression of BMP expression, the second being a
BMP-independent pathway. It will be interesting to
examine to which extent the proposed mechanisms are
conserved in mammals.
In addition to these early functions, FGFs promote
posterior neural fate during A/P patterning of the neural plate (35, 72, 96, 131, 165, 194). However, the
underlying molecular mechanisms are still largely unknown. Studies in Xenopus embryos have shown that
induction of posterior neural tissue mediated by the
transcription factors XBF2 and Xmeis3 requires the
activation of the FGF signaling-dependent Ras-MAP
kinase pathway (174). Studies in chicken embryos
have also shown that FGFs promote development of
posterior neural tissue by maintaining the proliferating neural progenitors contributing to posterior CNS
development (127). At later developmental stages, attenuation of FGF signaling is instead required to promote neuronal differentiation in the developing spinal
cord (33).
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ator of ANR function and acts in combination with
other ANR signals.
In contrast to the situation in the ANR, FGF8 is a
key mediator of the IsO functions. It is expressed by
the IsO cells when the IsO is active (embryonic days
8–12.5; Fig. 3A and Ref. 25). When FGF8 protein beads
are applied to different neural locations, for example
diencephalon and mesencephalon, FGF8 can induce
ectopic expression of genes normally present at the
mes-metencephalic junction and additional cerebellar
structures (26, 106, 123). Moreover, application of
FGF8 beads to the hindbrain rhombomere 1 shifts the
anterior boundary of the rhombomere 1 more posteri-
orly, as evidenced by changes in Hox gene expression
patterns (79). In agreement with these gain-of-function
studies, FGF8 loss-of-function mutations in zebrafish
and mice lead to IsO tissue loss (134, 171). In addition,
FGF8 zebrafish mutants lack cerebellar structure and
show patterning defects in the developing tectum and
its retinotectal projections (164, 171). Thus FGF8 secreted by the IsO cells influences cell specification,
leading to the induction and patterning of specific CNS
structures. Consistent with a role for FGF8 in cell fate
specification, FGF8 in combination with SHH and
FGF4 can induce dopaminergic and serotonergic neurons in neural plate explants (242). These and other
Fig. 3. Spatial distribution of Fgf8 and FGF2 during
patterning of the vertebrate CNS. A: distribution of
Fgf8 transcripts detected by whole mount in situ hybridization on a mouse embryo at embryonic day 9.25
(E9.25). Note the expression of Fgf8 by the anterior
medial cells of the telencephalon (arrowhead) and by
the isthimic organizer (IsO) cells (arrow). B: distribution of FGF2 proteins detected by whole mount antibody staining on a chicken embryo at stage 17 [staging
according to Hamburger and Hamilton (65)]. FGF2 proteins are present throughout the embryonic brain, and
protein levels are higher in the developing telencephalon and metencephalon (arrowheads). FGF2 proteins
are also found in the developing spinal cord (arrow). Ba,
branchial arch; FL, forelimb; HL, hindlimb; S, somite.
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Fig. 2. Fibroblast growth factor (FGF) 2 functions during development of the neuronal layers in the embryonic
neocortex. Left: schematic representation of a coronal section from an embryotic day 14 mouse brain at the level of
the lateral ventricles (LV). The rectangle indicates the approximate position of the enlargement shown on right.
Right: enlargement of the ventricular zone (VZ) and developing cortical plate (CP). During development of the
neuronal layers (NL) of the neocortex, progenitor cells in the VZ divide asymmetrically (M) to generate one
proliferating cell that remains in the VZ (arrowhead) and one postmitotic immature neuron. Postmitotic immature
neurons leave the ventricular zone and migrate toward the margin of the cerebral wall, where they form the
neuronal layers. Proliferating progenitors generate postmitotic neurons at precise time points. Neurons that
become postmitotic during early development will form the deep layers, whereas those leaving the cell cycle at later
stages will migrate through the existing cell layers and form more superficial ones. In FGF2-deficient mice, a
fraction of postmitotic neurons fail to reach their target neocortical layers. FGF2 is highly expressed by the cells
of the ventricular zone, indicating that FGF2 is part of the signaling network that determines the laminar fate of
postmitotic migrating neurons. GE, ganglionic eminence. Modified from Ref. 177.
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FGF PROTEINS AS REGULATORS OF NEOCORTEX
DEVELOPMENT
During mammalian CNS development, the neocortex arises from the dorsal telencephalon (Fig. 1B). This
structure will undergo rapid expansion by midembryogenesis so that it will become the predominant brain
structure (140). As development proceeds, the neocortex is partitioned into anatomically distinct areas
along the A/P and mediolateral axis. For example, the
motor and sensory cortices develop in the anterior and
the visual cortex develops more posterior (140). Neurons of the neocortex will also be organized into six
distinct layers running from the lumen of the neural
tube to the margin of the cerebral wall (130). These cell
arrangements have functional consequences, since
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neurons will develop synaptic connections according to
the position they occupy within the neocortical areas
and layers (130). It has been shown that growth and
patterning of the neocortex is strictly dependent on
localized production of instructive signals acting on the
progenitor cells, which lie near the lateral ventricle in
a layer known as the ventricular zone (VZ; Fig. 1B and
Ref. 130). Several studies have shown that FGFs are
among the regulatory signaling molecules. The expression of Fgfs and FgfRs in the developing mouse and rat
neocortices is spatially and temporally regulated. In
particular, the cells of the VZ express high levels of
FgfR1, FgfR2, and FgfR3 during the expansion of the
neocortical progenitor pool and throughout neurogenesis (37, 158, 160, 168). In agreement with receptor
distribution, FGF ligands are also found in the VZ. In
particular, FGF2 proteins are abundant at early developmental stages and nearly absent by the end of neurogenesis (37, 147, 167). Other FGFs, such as Fgf7 and
Fgf18, are also transiently expressed in the developing
neocortex [embryonic days 14.5–15.5 (75, 126)], and
their transcripts are found in the VZ and developing
cortical plate, respectively. In contrast to these, Fgfs,
Fgf8, and Fgf17 are predominantly expressed by the
anterior medial cells of the neocortical primordium
(Fig. 3A and Refs. 25 and 235), a signaling center for
neocortex A/P patterning (168). This suggests that
these FGFs might act as paracrine factors to regulate
development of the anterior neocortex. The biological
effects of FGFs on neocortical progenitor cells have
been first studied on cultured neocortical cells. FGF2
turned out to be among the most potent mitogenic and
survival factors for many CNS cell types, including
embryonic neocortical VZ cells (18, 169, 213, 214).
Other studies have shown that FGF2 acts either alone
or in combination with neurotrophins to promote differentiation of neocortical precursor cells (48, 144,
157). Finally, multipotential embryonic day 10 mouse
cortical cells will generate either neurons or astrocytes
in response to different concentrations of FGF2 in
culture media (166). Interestingly, other FGFs have
additional or distinct functions on neural progenitors.
For example, FGF8 can induce dopaminergic neurons
in explants of rostral fore- and midbrain, whereas
FGF4 and FGF2, but not FGF8, can ectopically induce
serotonergic neurons in midbrain explants (242). Moreover, FGF4 and FGF8b (an FGF8 isoform) promote
proliferation and survival of neuronal precursors,
whereas only FGF8b promotes differentiation along
the astrocyte lineage (63). The in vivo function of some
of these FGFs has been investigated by combining
embryonic manipulation with mouse molecular genetics. Genetic analysis of FGF2 functions in mice has
shown that FGF2 regulates neuronal density and cytoarchitecture of the developing neocortex (37, 153,
210). Neocortices of FGF2-deficient mice contain fewer
neurons at maturity (37, 153, 210) because of possible
defects in proliferation of progenitors (167). In addition, a fraction of postmitotic neurons fail to reach their
target layer in the developing neocortex of FGF2-deficient mice. These cells either remain in deeper layers
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findings have led to the proposal that FGF8 produced
by the ANR and the IsO, in combination with SHH and
FGF4, creates a grid of positional information in the
neural tube that specifies forebrain and midbrain dopaminergic neurons and hindbrain serotonergic neurons (242).
Fgf17 is also expressed by IsO cells after the onset of
Fgf8 expression (170, 236). Loss-of-function studies in
mice have shown that these FGFs cooperate in regulating cerebellar growth and shape by maintaining the
precursor cell pool in an undifferentiated proliferating
state (236). Interesting, FGF2 proteins are also present
in the metencephalon (Fig. 3B and Ref. 37), and a
single peripheral injection of FGF2 stimulates granule
cell production and enhances cerebellar growth in newborn rats (19). The IsO and its adjacent cell layers also
express Fgf18 and Fgf15, shortly after the onset of Fgf8
transcription (49, 125). Taken together, these observations suggest that at least four different FGFs may act
sequentially to determine the final size and shape of
the cerebellum.
In addition to control cerebellar development, FGFs
appear to have more general roles during patterning of
the vertebrate hindbrain. For example, it has been
proposed that FGFs participate in the establishment of
rhombomere identity during regionalization of the
hindbrain (Fig. 1 and Ref. 117). In zebrafish embryos,
signaling by rhombomere 4 cells influences segmental
identity and promotes neuronal differentiation of adjacent rhombomeres (129). The presumptive rhombomere 4 cells specifically express Fgf3 and Fgf8, and
development of rhombomere 5 and 6 is impaired by
blocking FGF3 and FGF8 functions (129, 218). These
studies indicate that FGF3 and FGF8 at the rhombomere 4 mediate the action of this signaling center in
promoting development of more caudal rhombomeres.
It is important to note that expression of Fgf3 in
rhombomere 4 is conserved among vertebrates (119,
120), whereas Fgf8 expression is not. This raises the
question whether this FGF-mediated signaling center
also functions in other vertebrates. The fact that Fgf3
is coexpressed with Fgf4 in chicken embryos (184)
suggests that other Fgfs may substitute for Fgf8 in
other species.
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FGFS IN THE DEVELOPING SPINAL CORD
Development of the spinal cord leads to the establishment of different neuronal cell types along its dorsoventral axis (14). For example, motoneurons will
differentiate ventrally, commissural neurons will form
dorsally, and neurons of the autonomic nervous system
will develop within the intermediate spinal cord layer
(14, 192). Spinal motoneurons innervate the muscles,
and their survival is dependent on trophic factors that
are produced by the targeted muscle cells and by the
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neuron itself (39). Several Fgfs (e.g., Fgf1 and -2 and -4
and -5) are expressed in the developing skeletal muscles (38, 66, 76) and by spinal motoneurons (e.g., Fgf1
and Refs. 9, 40, 83). Motoneurons also express FGFRs
(162, 220). In vitro, FGF2, FGF5, and FGF9 promote
survival of cultured chick and rat spinal motoneurons
(62, 76, 83) and FGF2 and FGF9 upregulate the choline
acetyltransferase (ChAT) activity in a dose-dependent
manner (62, 83). The biological effects of FGFs on
motoneurons have also been studied on experimentally
induced motoneuron damages and in animal models of
motoneuron diseases. As in vitro, also in vivo local
infusion of FGFs can rescue motoneuron death induced
by nerve fiber lesions (axotomy) or spinal cord injury
(28, 108, 206). However, levels of ChAT activity remain
low even in the presence of FGF2 (61). FGF2 also
mediates motoneuron survival in the wobbler mouse
affected by a motoneuron disease (78). FGF2-deficient
mice show neuronal deficiencies in the cervical spinal
cord region that also affect motoneuron density (37).
However, mice do not show apparent defects resulting
from the lack of a fraction of these motoneurons (37,
153, 244). Homozygous null Fgf9 mice die shortly after
birth, and motoneuron development has not been analyzed in these mice (24). Additional studies need to be
performed on these mutant strains to understand better if and how these FGFs contribute to motoneuron
development and function. It is likely that this process
requires a combination of different trophic factors,
among which are FGFs (14).
Physiological and pharmacological studies on FGF2deficient mice have shown that FGF2 is essential for
other spinal cord functions. In particular, lack of FGF2
causes an impaired baroreceptor reflex response to
hypotensive stimuli in adult mice (37). As a result of
the neuronal regulation defect, FGF2-deficient mice
show a reduced resting arterial blood pressure (37,
244). During CNS development, Fgf2 is expressed by
progenitor cells of neuronal circuits involved in the
central regulation of blood pressure, for example, in the
myelencephalon (Fig. 3B and Ref. 36) and the intermediolateral neurons of the spinal cord (192). Reexpression of FGF2 in the developing nervous system of
FGF2-deficient embryos leads to a rescue of the baroreceptor reflex and of the hypotensive phenotype (36).
These genetic studies indicate that FGF2 signaling is
essential for development of the neural circuitry regulating central regulation of blood pressure (36). The
distribution of certain classes of neurons of the intermediate cell layer is affected in FGF2-deficient embryos (E. ten Hove and R. Dono, unpublished observations), suggesting that positional identity of spinal cord
neurons may be altered.
FGFS IN BRAIN PHYSIOLOGY AND PATHOLOGY
Most of the Fgf family members and Fgf receptors
remain expressed in different cell types of the adult
brain (Fig. 4 and Refs. 50, 69, 70, 189, 193, 233, 241).
A number of recent studies are beginning to address
the role of FGFs in brain physiology and pathology.
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or accumulate in the corpus callosum (37). These genetic studies show that lack of FGF2 affects cell positioning in the developing neocortex. Development of
the neuronal layers of the neocortex begins once newly
generated postmitotic neurons leave the VZ and migrate to the cortical plate. It has been shown that the
migratory paths of postmitotic neurons are defined by
instructive signals acting on the progenitors in the VZ
as these cells undergo their last mitotic division (130).
Signals also act in the cortical plate and direct laminar
organization of migrating neurons. Neuronal cells are
exposed to FGF2 before or during onset of neuronal
migration (Fig. 2 and Ref. 37). Indeed, FGF2 is expressed at high levels by the cells of the VZ, whereas it
is not expressed by migrating neurons or other cortical
plate cells (37). Thus it is likely that FGF2 is part of the
signaling network that acts on the progenitor cells and
defines the cell fate and migratory path of postmitotic
neurons (Fig. 2).
The neuronal defects observed in FGF2-deficient cortices predominantly affect the frontal motor sensory
areas (37, 153, 211). This observation raises the possibility that FGFs are part of the signaling network
regulating differential growth and patterning of neocortical areas. As discussed above, Fgf8 is expressed by
the anterior medial cells of the telencephalon (25).
Fukuchi-Shimogori and Grove (44) have shown that
anterior expansion of the FGF8 source shifts the
boundaries of the cortical areas more posterior,
whereas reducing the endogenous FGF8 signal shifts
these boundaries more anterior. Moreover, an ectopic
posterior source of FGF8 instructs surrounding cells to
acquire anterior identity. It is important to note that
no changes in cortical size were observed in these
experiments. Thus Fgf8 appears to specify positional
identity in the neocortical primordium without affecting cell proliferation (44). Regional specification of the
neocortical neural stem cells is mediated by gradients
of transcriptional regulators such as Emx2 and Pax6.
In particular, Emx2 is expressed at high levels by
neocortical progenitors of the posterior VZ and at low
levels by those of the anterior VZ. In contrast, Pax6 is
high in the anterior VZ and low in the posterior (12,
121). FGF8 beads applied to the dorsal telencephalon
of developing chicken embryos inhibit Emx2 expression (27). It will be important to understand whether
FGF8 regulates regionalization of the neocortex by
acting on these transcription factors or on other unknown regulators.
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Most studies have focused on the possibility that
FGF2 acts as a neurotrophic factor on mature brain
neurons. For example, several laboratories have
shown that FGF2 can promote survival of neocortical, hippocampal, cerebellar, dopaminergic, spinal
cord, and sensory neurons isolated from adult CNS
(1, 13, 60, 95, 116, 128). The neuronal survival promoted by FGF2 is independent of its mitogenic activity for glial cells (217). However, studies on FGF2deficient mice have failed to reveal an increased cell
death in the brain of embryos and adults (37, 167).
Interestingly, FGF2 levels increase after CNS damage (50, 59), ischemia (47, 243), or seizure (243).
Changes in FGF2 levels are also observed in patients
with neurodegenerative disorders, such as Alzheimer’s and Parkinsons’ diseases (52, 207). These observations raise the possibility that FGF2 acts to
protect the brain from pathological events, where it
promotes survival and/or has additional effects on
neural cells. The biological effects of FGF2 in response to brain damage are currently being tested
using a variety of experimental systems. As discussed above, neuronal cell death can be induced in
vivo by performing axotomy. Peterson et al. (161)
have shown that axotomy-induced death of glutamatergic neurons is prevented by grafting fibroblasts
expressing FGF2 before axotomy. Brain damage can
also be induced by injecting kainic acid, which causes
seizures and neuronal cell death (113). When FGF2
is infused in the rat brain before seizure, it can
prevent cell loss in the hippocampal region (113).
FGF2 seems to rescue the injured neurons and promote brain regeneration through multiple strategies.
Infusion of antibodies against FGF2 in the lateral
ventricles leads to a significant reduction in sprouting of cholinergic neurons within a denervated hippocampus (41). These results are consistent with
AJP-Regul Integr Comp Physiol • VOL
neurite-promoting effects of FGF-2 on cultured cholinergic neurons (6, 154). Progenitor cells of the
hippocampus proliferate and differentiate in response to cerebral ischemia or seizures (110, 111,
201). Yoshimura et al. (243) have demonstrated that
this process is affected in FGF2-deficient mice. Neurogenesis is restored upon delivering exogenous
FGF2 to the hippocampus before cerebral ischemia
and/or seizures (243). The molecular mechanisms
underlying the potential FGF2-mediated repair of
damaged brain cells are still unknown. Lenhard et
al. (107) have shown that the neuroprotective effects
of FGF2 on glutamate-induced hippocampus lesions
are in part mediated by glial cell-derived neurotrophic factors. Instead, the neuroprotective action of
FGF2 in stroke-induced cell death is dependent on
the induction of activin A (208).
The potential use of FGF2 for treatment of brain
disorders is very attractive. Clinical trials of intravenous administration of FGF2 for treatment of
acute stroke are in progress (8, 9). However, further
studies are required to determine if FGF2 is an
efficient therapeutic reagent for treatment of disorders affecting the adult brain. Direct insight into a
more general role for FGFs in brain physiology and
pathology will come from detailed analysis of mouse
mutant strains carrying loss-of-function mutation of
FGFs or FGFRs expressed in the adult brain. Indeed,
genetic analysis of FGF14 functions has shown that
FGF14-deficient mice develop ataxia and hyperkinetic movement disorders similar to those found in
patients affected by Huntington’s disease, Parkinson’s disease, and dystonia (222). These motor abnormalities are associated with dysfunction of the
basal ganglia system and result from defects in axonal trafficking and synapsis.
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Fig. 4. Distribution of FGF2 proteins in the adult
mouse brain. A: FGF2 proteins were detected by whole
mount antibody staining on a coronal cryosections of an
adult mouse brain, using FGF2-specific antibodies (38).
The highest levels of FGF2 proteins were found in the
hippocampal pyramidal neurons of the CA1 region
(CA1) and in astrocytes (arrows). The staining in the
corpus callosum (CC) is nonspecific, as determined by
using control cryosection of adult FGF2-deficient mouse
brains. The rectangles indicate the approximate position of the enlargements shown in B and C. B: enlarged
view showing FGF2-positive hippocampal pyramidal
neurons of the CA1 region. C: enlarged view showing
FGF2-positive astrocytes (arrowheads) at the level of
the dentate gyrus (DG). Nx, neocortex.
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FGFS AND THE NEURAL STEM CELLS IN THE
ADULT CNS
AJP-Regul Integr Comp Physiol • VOL
CONCLUSIONS AND FUTURE DIRECTIONS
Research over the past years has advanced our understanding of the role of FGF signaling in the embryonic and adult CNS. These studies have shed light on
the role of FGFs during neural induction, patterning of
specific CNS regions, and in the establishment of functional neuronal circuits. However, several major issues
remain unanswered. The gene targeting approach in
mice and analysis of zebrafish mutants have clarified
the functions of some of the Fgfs expressed by neural
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For many years, the adult brain was wrongly considered an entirely postmitotic structure. More recently,
research has corroborated previous findings by Altman
and coworkers (4, 45, 84, 86, 98, 205) that established
that specific areas of the adult brain retain the capacity
for neurogenesis. Neurogenesis occurs in at least two
sites of the adult brain: the subgranular zone of the
hippocampus (3, 85) and the telencephalic subventricular zone (SVZ; 94, 114, 118). The subgranular zone
generates the granule cells of the hippocampus (85, 86,
191), whereas the SVZ is the source of new olfactory
bulb neurons (93, 114, 115, 118). Genesis of neurons
has also been reported in the primate prefrontal cortex,
temporal cortex, and parietal cortex (4, 54, 84), and it
has been proposed that the SVZ might also be the
source of these neurons (4, 54, 84). Neurogenesis in the
adult brain relies on neural stem cells (29, 90, 172,
225). Neural stem cells are defined as undifferentiated
cell types that undergo self-renewal and thereby retain
their multilineage potential (132). Recently, neural
stem cells have been isolated from many CNS regions,
including the previously mentioned neurogenic zones
and nonneurogenic regions, such as the spinal cord (30,
90, 141, 225). In vitro, proliferating neural stem cells
form aggregates, so-called neurospheres, that maintain both the capability of self-renewal and the ability
to differentiate into neurons, astrocytes, and oligodendrocytes (46, 55, 173, 209, 213, 225). It has been shown
that the in vitro expansion and differentiation of neural stem cells can be regulated by adding extracellular
factors to the culture medium (46, 55, 58, 80, 156, 209,
213, 225). FGF2 and EGF are the most potent mitogens
and survival factors for cultured neural stem cells (46,
141, 172, 173, 209, 213, 225). For example, FGF2 and
EGF have been used both alone and in combination to
isolate and maintain stem cells of the adult SVZ and
the spinal cord in culture (55, 56, 141, 173, 187, 225).
FGF2 alone is sufficient to maintain neural stem cells
from either the adult striatum (57) or hippocampus
(46) of rodents. Taupin et al. (204) have recently shown
that cystatin C, a cystein proteinase inhibitor, is able
to potentiate the mitogenic activity of FGF2 and enables expansion of rat hippocampal neural stem cells
from single cells. It will be interesting to examine if
cystatin C also cooperates with FGF2 to promote proliferation of neural stem cells isolated from other CNS
regions.
One major question in stem cell biology concerns the
type of progeny that neural stem cells can generate.
Differentiation of cultured neural stem cells can be
induced by mitogen withdrawal or by addition of extracellular factors that will drive differentiation along
the neuronal or glia cell lineage (58, 80, 202). However,
it is not clear whether differentiating neural stem cells
are able to generate functional neuronal subtype, such
as GABAergic interneurons or cortical pyramidal neurons, in addition to differentiation of a generic neuronal phenotype. Recent studies using FGF2-responsive
hippocampal neural stem cells show that these cells
can differentiate into cells with phenotypes of GABAergic, dopaminergic, and cholinergic neurons when exposed to both retinoic acid and neurotrophins (202). In
addition, forced expression of the orphan nuclear receptor Nurr1 (104) in these cells induces predominant
differentiation of tyrosine hydroxylase (TH)-positive
dopaminergic neurons (178, 215).
Another way of testing the developmental potential
of neural stem cells in vivo is their reimplantation in
the adult CNS (15, 16). Suhonen et al. (197) have
demonstrated that cultures of adult rat hippocampal
neural stem cells undergo neuronal differentiation
only when implanted in neurogenic sites. When transplanted in the hippocampus, cells that migrate to the
neuronal layer of the dentate gyrus give rise to hippocampal-like neurons. In contrast, hippocampal progenitors differentiate into TH-positive neurons, a
marker for dopaminergic neurons, when implanted in
the rostral migratory stream leading to the olfactory
bulb (197). As discussed previously, neural stem-like
cells can be cultured from the adult spinal cord in the
presence of FGF2 (187). Shihabuddin et al. (186)
showed that these cells, although isolated from a nonneurogenic region, exhibit a broad developmental potential upon exposure to different environmental stimuli. Spinal cord neural stem cells give rise to glial cells
if transplanted back into the adult spinal cord. When
transplanted in the hippocampus, cells that integrate
in the neuronal layer of the dentate gyrus differentiate
into hippocampal-like neurons of the granular cell
layer (186). Alternatively, they acquire an astroglial
and oligodendroglial phenotype when integrated in
nonneurogenic regions of the hippocampus (186).
These studies indicate that neural stem cells expanded
in the presence of FGF2 retain pluripotency and integrate into the host tissue where they respond to local
differentiation signals.
The possibility that FGF2 may also promote proliferation of neural stem cells in vivo is currently being
investigated. For example, Wagner et al. (216) have
shown that subcutaneous injection of FGF2 increases
the number of proliferating cells in the SVZ and olfactory tract. Injection of FGF2 in the lateral ventricle of
an adult rat brain expands the SVZ progenitor pool and
increases the number of neurons in the olfactory bulb
(99). Finally, combined injection of FGF2 and cystatin
C to the adult dentate gyrus stimulates proliferation
and neurogenesis in the adult rat hippocampus (204).
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I am grateful to Liliana Minichiello and Klaus Unsicker for
discussion on Fig. 4. I also thank Jacqueline Deschamps, Rolf Zeller,
and members of the laboratory for critical comments that have
improved this manuscript. I apologize to many researchers in this
fast-moving field whose work I have not cited because of space
limitations.
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