1 Institute of Biomedicine, University of Helsinki, PO Box 63 (Haartmaninkatu
8), FIN-00014 and HUCH Laboratory Diagnostics, PO Box 400, Helsinki University
Central Hospital, FIN-00029, Finland
2 Institute of Biotechnology, University of Helsinki, PO Box 56 (Viikinkaari 9),
University of Helsinki, FIN-00014, Finland
* Author for correspondence (e-mail: hannu.sariola{at}helsinki.fi)
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Summary |
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Key words: Glial-cell-line-derived neurotrophic factor, RET receptor tyrosine kinase, Met receptor tyrosine kinase, GDNF family receptor , NCAM, Neuronal survival, Kidney morphogenesis, Spermatogenesis
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Introduction |
---|
GDNF and the related GFLs artemin (ARTN), neurturin (NRTN) and persephin
(PSPN) support several neuronal populations in the central nervous system,
including midbrain dopamine neurons and motoneurons. In addition, GDNF, NRTN
and ARTN promote the survival and regulate the differentiation of many
peripheral neurons, such as sympathetic, parasympathetic, sensory and enteric
neurons (reviewed by Airaksinen et al.,
1999; Manié et al.,
2001
; Airaksinen and Saarma,
2002
).
GDNF has several roles outside the nervous system. It functions as a
morphogen in kidney development and regulates spermatogonial differentiation.
In the embryonic kidney, GDNF acts as a mesenchyme-derived signal promoting
ureteric branching. In the testis, the GDNF dosage controls the cell fate
decision of undifferentiated spermatogonia (reviewed by
Saarma and Sariola, 1999;
Airaksinen and Saarma,
2002
).
The cellular responses to GFLs are mediated by a multicomponent receptor
complex consisting of RET receptor tyrosine kinase and a glycosyl
phosphatidylinositol (GPI)-linked ligand-binding subunit known as GDNF family
receptor (GFR
). Several recent in vitro findings demonstrate
that GFLs also signal independently of RET, and in particular through NCAM.
Here we focus on the new receptors for GDNF and the functional
implications.
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GDNF receptors |
---|
|
RET activates several intracellular signalling cascades, which regulate
cell survival, differentiation, proliferation, migration, chemotaxis,
branching morphogenesis, neurite outgrowth and synaptic plasticity. The MAP
kinase pathway may be involved in ureteric branching during nephrogenesis
(Fisher et al., 2001) and
neurite outgrowth in the nervous system, but it also contributes to neuronal
survival (Kaplan and Miller,
2000
). The phosphoinositide 3-kinase (PI3K) pathway is crucial for
both neuronal survival and neurite outgrowth. The phospholipase C
(PLC-
) pathway regulates the intracellular level of Ca2+
ions by increasing the level of inositol (1,4,5)trisphosphate. GDNF signalling
also employs Src-family kinases, which elicite neurite outgrowth, neuronal
survival and ureteric branching (Airaksinen
and Saarma, 2002
). In most cases tyrosine residues Tyr905,
Tyr1015, Tyr1062 and Tyr1096 of RET are phosphorylated, but after the
elevation of cyclic AMP levels, Ser696 is also phosphorylated. Protein kinase
A (PKA)-dependent Ser696 phosphorylation is important for GDNF-induced Rac
activation and lamellipodia formation
(Fukuda et al., 2002
). RET
contains additional tyrosine residues that are phosphorylated upon GFL binding
(Tyr687, Tyr826 and Tyr 1029), but the role of these in GFL signalling remains
obscure.
RET activation affects different downstream targets inside and
outside lipid rafts (the dynamic assemblies of cholesterol and sphingolipids
scattered within the disordered phase of the lipid bilayer). Lipid rafts are
proposed to serve as essential signalling compartments in the cell membrane,
and are important for cell adhesion, axon guidance and synaptic transmission.
GPI-anchored proteins, certain transmembrane proteins, doubly acylated
proteins, and cholesterol-linked and palmitoylated proteins are enriched in
the rafts. However, the protein motifs responsible for their targeting to
lipid rafts are largely unknown. The GFR proteins, by the virtue of
their GPI anchors, also localize to lipid rafts. Inactive RET is outside
rafts, and only upon GDNF stimulation does GFR
1 recruit RET into lipid
rafts; the mechanism is unknown. Soluble GFR
1 also targets RET to lipid
rafts (reviewed by Paratcha and
Ibañéz, 2002
;
Tsui-Pierchala et al., 2002a
).
Moreover, it prolongs GDNF-mediated activation of cyclin-dependent kinase 5
(CDK5) and acts as an attractive guidance signal for axons
(Ledda et al., 2002
).
Activated RET is preferentially associated with the adaptor SHC outside rafts,
and with FGF receptor substrate 2 (FRS2) in rafts
(Paratcha and Ibañéz,
2002
). These data suggest that differences in GDNF signalling
through RET within and outside the rafts could lead to dramatically different
cellular responses.
RET is alternatively spliced, producing at least two isoforms,
RET9 and RET51, which differ only in their C-termini. Recent evidence suggests
that RET9 and RET51 do not associate with each other. Furthermore, RET51- and
RET9-associated signalling complexes are markedly different
(Tsui-Pierchala et al.,
2002b). The long isoform, RET51, associates more strongly with the
ubiquitin ligase Cbl than does RET9, which leads to faster turnover of RET51.
RET51 also interacts with the adaptor Crkl, producing sustained activation of
Erk1 and Erk2 (R. P. Scott, Signal transduction mechanisms mediated by the
GDNF family ligands and receptors, PhD thesis, Karolinska Institute,
Stockholm, 2002). Mice lacking the long RET isoform seem to be normal, whereas
mice lacking the short isoform have kidney abnormalities and enteric
aganglionosis. Only the short RET9 isoform can rescue the phenotype of the
RET-null mutation in the kidney and enteric nervous system
(de Graaf et al., 2001
).
GFLs belong to the transforming growth factor-ß (TGF-ß)
superfamily, although the amino acid sequence similarity between them is low.
Surprisingly, the neurotrophic effect of GDNF in vitro and in vivo, except for
motoneurons, requires the presence of TGF-ß
(Peterziel et al., 2002).
Blocking the ERK/MAPK pathway inhibits this co-operative effect, whereas
inhibition of the PI3K signalling does not. Pre-treatment of primary neuronal
cultures with TGF-ß confers GDNF responsiveness on the cells. This is not
due to upregulation of GDNF receptor mRNA and protein but to
TGF-ß-induced recruitment of the GFR
1 to the plasma membrane. In
the absence of TGF-ß, GDNF supports neuronal survival if the soluble form
of GFR
1 is present. Thus, TGF-ß is involved in GFR
1
membrane translocation and in a novel way regulates GDNF signalling and
neurotrophic effects. It would be of great interest to know whether TGF-ß
also regulates other GFR
proteins.
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GDNF signalling requires glycosaminoglycans |
---|
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GDNF can signals independently of RET |
---|
|
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NCAM is the second signalling receptor for GFLs |
---|
The ability of GFR1 to modulate NCAM-mediated cell adhesion even in
the absence of GDNF suggests independent roles for GFR
1-NCAM and
GDNF-GFR
1-NCAM signaling. By binding to NCAM, GDNF stimulates Schwann
cell migration and axonal growth in hippocampal and cortical neurons in a
RET-independent fashion. These findings suggest that GFR
proteins and
GFLs, interacting either together or alone with NCAM, use different signalling
pathways to modulate both short- and long-range intercellular communication.
Further studies are needed to reveal the in vivo roles of GDNF-NCAM and
GDNF-GFR
-NCAM signalling, and to dissect the specific contribution and
possible interplay of both RET and NCAM in signalling by GFLs. A recent study
demonstrating that both in vitro and in vivo effects of GDNF on midbrain
dopaminergic neurons are inhibited by an NCAM-blocking antibody further
supports the physiological relevance of GDNF signalling through NCAM
(Chao et al., 2003
).
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Ret signals independently of GFLs |
---|
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GDNF regulates ureteric branching |
---|
|
Tissue culture studies have further implied that, although GDNF is
essential for ureteric bud branching, other mesenchyme-derived signals are
required. If microsurgically isolated ureteric buds are exposed to GDNF, they
do not undergo branching. When such buds are recombined with heterologous
mesenchyme, such as lung mesenchyme, the ureteric buds branch in response to
GDNF (Sainio et al., 1997).
The identity of this factor expressed by embryonic mesenchyme is unknown but,
in cultures of isolated ureteric buds, heparin-binding growth-associated
molecule (also known as pleiotrophin/osteoblast-stimulating factor 1) is
required for GDNF-induced branching morphogenesis
(Qiao et al., 1999
).
Heparan sulphate proteoglycans may also be important for GDNF signalling in
embryonic kidneys, because the effect of depriving kidneys of heparin
sulphates is similar to that of knocking out GDNF or RET
(Bullock et al., 1998). The
transcription factors Pax2 and Eya1 control GDNF expression in differentiating
nephrogenic mesenchymal cells (Xu et al.,
1999
; Brophy et al.,
2001
), whereas expression of RET by ureteric bud cells is
indirectly regulated by retinoic acid
(Batourina et al., 2001
). NRTN,
GFR
2 and NCAM are also expressed in the developing kidney, but they
have no renal phenotype when knocked out
(Cremer et al., 1994
;
Heuckeroth et al., 1999
;
Rossi et al., 1999
).
Therefore, their in vivo roles in renal differentiation remain unclear.
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... and spermatogenesis |
---|
|
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RET receptor tyrosine kinase and GDNF in diseases |
---|
Various factors influence the type of RET mutation found in different
cancers, such as exposure to radiation, age and the histological type of the
tumour. In medullary thyroid cancer, germline RET mutations are found
in practically all familial cases, and somatic point mutations occur in nearly
half of the sporadic cases. Papillary thyroid carcinomas (PTC) frequently show
gene rearrangements, which give rise to chimeric genes referred to as
RET/PTC. These rearrangements occur in almost half of papillary
cancers (Hansford and Mulligan,
2000; Takahashi,
2001
). Since both RET and Met are pathologically activated in
various cancer forms, it is tempting to speculate about their possible
synergistic effect in carcinogenesis.
Inactivating mutations in RET are common in Hirschsprung's
disease, which is characterized by the absence of neuronal ganglia in various
parts of the colon, leading to severe constipation and intestinal obstruction
during childhood. Estimates of the frequency of RET mutations in
Hirschsprung's patients vary, ranging in different populations from 5% to 50%
(reviewed by Newgreen and Young,
2002). RET mutations are more common in the familial form than in
sporadic Hirschsprung's disease. GFR
mutations have not been
found in Hirschsprung's patients (Borrego
et al., 2003
), and they are unexpectedly not significant in the
pathogenesis of the disease. Studies on the role of GDNF mutations in
the pathogenesis of Hirschsprung's disease seem contradictory. Heterozygous
GDNF+/- mice develop Hirschsprung-type intestinal obstruction
(Shen et al., 2002
), and four
different mutations have been found in Hirschsprung's disease. At least two of
them reduce the affinity of GDNF for GFR
1
(Eketjäll and Ibañéz,
2002
). However, these GDNF mutations do not reduce the activation
of RET (Borghini et al., 2002
;
Eketjäll and Ibañéz,
2002
). NRTN has also been linked with the pathogenesis of
Hirschsprung's disease. A mutation in NRTN has been found in a large
pedigree with the disease. The mutation is not sufficient to cause
Hirschsprung's disease but modifies the disease severity caused by a
RET mutation in the pedigree
(Doray et al., 1998
).
Hirschsprung disease is a multigenic disease already associated with eight
disease loci. The disease phenotype is modulated by genetic interactions
between two or more disease genes, and there is low penetrance. Molecular
genetic analyses have revealed that, in particular, the interaction between
mutations in the genes encoding RET and endothelin receptor B (EdnrB) are
central to the pathogenesis of Hirschsprung disease
(Carrasquillo et al., 2002).
In accordance with this, RET+/- heterozygous mice show no
intestinal aganglionosis and EdnrB-null homozygotes show
agangliononsis only in the very distal colon. When the
RET+/- mice are crossed with mice carrying different
combinations of EdnrB-null allele, the decreasing dosage of EdnrB
dramatically increases the length of aganglionosis
(MacCallion et al., 2003
).
Thus, genetic crosstalk between EdnrB and RET is essential for both normal
development of the enteric nervous system and the pathogenesis of Hirschsprung
disease.
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Perspectives |
---|
GDNF is currently the most potent protein for the treatment of the Parkinson's disease. However, the molecular events leading to the degeneration of dopaminergic neurons are largely unclear. Importantly, death pathways activated in dopaminergic neurons by removal of neurotrophic factors, and GDNF in particular, have not been studied. Unravelling the intracellular cascades that are activated in GDNF-deprived dopaminergic neurons would offer a unique opportunity to develop pharmacological inhibitors that specifically block these death pathways but leave other pathways untouched. Use of low-molecular-weight drugs in therapy may be an interesting alternative to recombinant neurotrophic factors.
Other GFLs may also have therapeutic potential. Recent studies demonstrate
that, in a rat model of Parkinson's disease, PSPN delivered to the brain by
neural stem cells is as efficacious as GDNF at promoting both survival and
neuritogenesis of midbrain dopamine neurons
(Åkerud et al., 2002).
Because the expression of PSPN receptor GFR
4 is much more restricted
than that of the GDNF receptor GFR
1
(Lindahl et al., 2000
), it is
logical to assume that PSPN, even if used at higher concentration, would cause
fewer side-effects than GDNF.
GFLs may also become useful for the treatment of drug addiction. It is well
established that chronic administration of cocaine and morphine induce
neurobiological changes in the ventral tegmental area (VTA) of the rat and
mouse brain, the origin of the mesolimbic and mesocortical dopaminergic
neurons. In animal studies, infusion of the VTA with GDNF blocks certain
biochemical adaptations to chronic cocaine and morphine administration, as
well as to the rewarding effects of cocaine. Most interestingly, chronic
cocaine and morphine administration decreases RET-phosphorylation levels,
suggesting that these drugs decrease signalling through endogenous GDNF
pathways in the VTA (Messer et al.,
2000). Although information about intracellular cascades triggered
by GFLs is rapidly emerging, nothing is known about the
neurotrophic-factor-induced signalling pathways involved in drug addiction.
Since, in addition to GDNF, NRTN and PSPN protect dopaminergic neurons in the
animal models of Parkinson disease, it will be of great interest to study
whether NRTN and/or PSPN signalling can regulate adaptations to abused
drugs.
The role of GDNF in the control of spermatogenesis is also intriguing, because GDNF is the first molecule that is known to control the cell fate decision of spermatogonial stem cells. GDNF signalling is therefore an attractive target for the development of male contraceptives. However, such efforts are severely shadowed by the carcinogenic consequences of deregulated RET activation.
The recently identified new GFL receptor NCAM, as well as crosstalk between
GDNF-GFR1-MET and NGF-TrkARET, make GDNF biology unexpectedly
complicated. Horizontal interplay of unrelated receptor systems is being
increasingly identified and undermining the classic view of the
ligand-receptor interaction as a one-way event. In spite of this complexity,
GFLs offer a unique opportunity for development of drugs for treatment and
possibly prevention of several diseases, particularly neurodegenerative
diseases. However, GFL proteins are difficult and expensive to produce, they
are often labile and their delivery to the target is complicated by the fact
that they do not cross the blood-brain barrier. Therefore the next challenge
is to find low-molecular-weight drugs that affect intracellular signalling
pathways involving and mimicking the action of natural neurotrophic factors.
The development of such drugs will be dependent on detailed understanding of
the 3D structure of GFLs and their receptors, as well as the molecular,
cellular and pathological aspects of their signalling mechanisms.
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Acknowledgments |
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