616

Studies of neurotrophins and Trk receptors in jawless fish have

shed light on the course of events underlying the formation of
these gene families. They evolved early in vertebrate history
during major gene duplication events, before the appearance
of cartilaginous fish. The existence of multiple genes has
permitted the diversification of neurotrophin and Trk receptor
expression, and thereby enabling the acquisition of specific
functions in selective neuronal populations.
Addresses
Department of Neuroscience, Biomedical Center, Uppsala University,
Husargatan 3, Box 587, S-751 23 Uppsala, Sweden;
e-mail: Finn.Hallbook@neuro.uu.se
Current Opinion in Neurobiology 1999, 9:616621
0959-4388/99/$ see front matter 1999 Elsevier Science Ltd.
All rights reserved.
Abbreviations
BDNF brain-derived neurotrophic factor
HSA human chromosome
Lf-NT Lampetra fluviatilis neurotrophin
Mg-NT Myxine glutinosa neurotrophin
NGF nerve growth factor
NT neurotrophin
p75 low-affinity NGF receptor
RTK receptor tyrosine kinase
Introduction
The neurotrophins are structurally related neurotrophic
polypeptide factors that regulate neuronal differentiation,
survival, neurite growth and plasticity [1]. The family
includes nerve growth factor (NGF), brain-derived neu-
rotrophic factor (BDNF), neurotrophin-3 (NT-3) and
neurotrophin-4/5 (NT-4/5) also known as just NT-4 and
NT-5. To date, neurotrophins have been isolated only from
chordates. NGF, BDNF, NT-3 and NT-4/5 have been
found in all the major classes of tetrapods [2], except for
NT-4/5, which has not been found in birds. The situation
is more complex in fish: NGF, BDNF and NT-3, as well as
two additional neurotrophins related to NGF (denoted
NT-6 [3] and NT-7 [4

,5

]), have been isolated from bony

fish species, whereas BDNF and NT-3 have also been
found in cartilaginous fish. Recently, we [6

] isolated a
neurotrophin from the river lamprey (Lampetra fluviatilis
neurotrophin [Lf-NT] and another one from the Atlantic
hagfish (Myxine glutinosa neurotrophin [Mg-NT]). The lam-
preys and hagfish are jawless fish that diverged early in
vertebrate history, some 460 million years ago [7,8

].
Neither Lf-NT nor Mg-NT display any close similarity to
the other neurotrophins.
The neurotrophins bind two types of receptors: the tyro-
sine kinase Trk receptors and the low-affinity NGF
receptor p75, which is a member of the tumour necrosis
receptor superfamily. The function of p75 is less well
understood than that of the Trk receptors [9,10]. The Trk
receptors mediate specificity and several of the neu-
rotrophic functions of the neurotrophins. There are three
main types of Trk receptors: TrkA is a receptor for NGF,
NT-6 and NT-7; TrkB a receptor for BDNF and NT-4/5;
and TrkC is a receptor for NT-3 [1]. Two additional verte-
brate Trk receptors, which are different from TrkA, TrkB
and TrkC, have been isolated from lamprey (L. fluviatilis)
[6

]. The neurotrophin affinities for these L. fluviatilis Trk

receptors (Lf-Trk1 and Lf-Trk2) have not been determined,
but it is likely that Lf-NT binds to at least one of them.
Phylogeny of vertebrate neurotrophins and Trk
receptors
The molecular phylogeny of neurotrophin and Trk recep-
tor sequences suggests a course of events for the formation
Evolution of the vertebrate neurotrophin and Trk receptor
gene families
Finn Hallbk
Figure 1 legend
Schematic illustration of the phylogenetic relationship between jawless
fish, jawed fish, and the common vertebrate lineage, showing the
suggested gene duplications leading to the extant vertebrate
neurotrophin and Trk receptor gene homologues. (a) Inferred
consensus tree based on neurotrophin amino acid sequences from
representative species. (b,d) Illustrate the divergence of branches
representing jawless fish (Agnatha), cartilage fish (Chondrichtyes) and
one bony fish lineage (Osteichtyes) from the tetrapod lineage. The
neurotrophin (b) and Trk receptor (d) gene families are illustrated
within the branches, with suggested duplications depicted as line-
forks. Two subsequent duplication events are indicated in the early
chordate/vertebrate lineage, with the second duplication taking place
after the divergence of lampreys (Cephalaspidomorphi) but before the
divergence of cartilaginous fish. An additional duplication is suggested
in the osteichtyesan lineage, giving rise to the hitherto found NGF,
TrkB and TrkC paralogues in bony fish. The dates of the divergence of
ancestors to extant jawless and bony fish from the common vertebrate
lineage are based on fossil records [7]. (c) Consensus tree based on
Trk receptor sequences, including Lf-Trk1 and Lf-Trk2. The depicted
inferred consensus trees (a,c) are bootstrap consensus trees and were
generated using PAUP v.3.1.1 (Phylogenetic Analysis Using
Parsimony, program and manual distributed by Illinois Natural History
Survey, Champaign, Illinois) from 500 unrooted branch-and-bound
replicates of the most parsimonious trees with sampling excluding
uninformative characters. Bootstrap percentages are indicated on
branches in the tree and indicate how often a particular branch was
found in the bootstrap analysis. If a branch was found in less than 50%
of the trees, it was collapsed into a polytomy. The consensus trees only
show the relations between the taxa, and branch lengths do not reflect
distances between taxa. The shortest trees found when analyzing the
matrices had all high consistency index values (c.i. NT tree = 0.832
and Trk tree = 0.844), indicating a low degree of homoplasy. MYBP,
million years before present. (b,d) Adapted from [6

].
nb9507.qxd 10/25/1999 8:30 PM Page 616
Evolution of the vertebrate neurotrophin and Trk receptor gene families Hallbk 617
of the neurotrophin and Trk gene families, which is illus-
trated in Figure 1. Two duplications led to the formation of
NGF, NT-3, BDNF and NT-4/5 (Figure 1a). NGF and
NT-3 were formed by the duplication of one intermediate
neurotrophin ancestral gene, whereas BDNF and NT-4/5
came from another intermediate ancestor. These duplica-
tions took place before the split of cartilaginous fish but
after the split of lampreys and hagfish from the common
vertebrate lineage. Thus, Lf-NT and Mg-NT arose before
the gene duplications and are descendants of the interme-
diate neurotrophin ancestors. This course of events
suggests the existence of an additional neurotrophin in
lamprey and hagfish. The inferred neurotrophin and Trk
trees (Figure 1a,c) are similar in many respects, suggesting
that the Trk genes were formed during a course of events
similar to that of the neurotrophins. According to this
model, trkA and trkC were formed by the duplication of an
intermediate ancestral trk gene. Lf-trk1 is probably a
descendant of the intermediate trkA/C ancestor.
The timing of these duplications early in vertebrate history
parallels that of several other gene families [11,12,13

].
Figure 1
TrkA
TrkC
TrkB
Lf-Trk1 Myxine
Lampetra
Ancestral Trk
TrkA/TrkC ancestor
TrkB ancestor
Chondrichtyes
Osteichtyes
Tetrapods
Lf-Trk2
TrkB
TrkA
TrkC1
TrkB1
TrkC2 TrkB2
NGF
NT-3
BDNF
NT-4/5
NGF
NT-3
BDNF
(NGF)
NT-3 BDNF
Mg-NT Lf-NT
Myxine
Lampetra
Ancestral neurotrophin
NGF/NT-3 ancestor
BDNF/NT-4 ancestor
Chondrichtyes
Osteichtyes
Myxini
Cephala-
spidomorphi
Agnatha
Agnatha
NT-7
(NT-4/5)
Tetrapods
Additional
duplication
Additional
duplication
NT-6
(a) (b)
Neurotrophin evolution
Trk receptor evolution
TrkC
TrkA
> 460 MYBP
> 400 MYBP
> 360 MYBP
> 460 MYBP
> 400MYBP
> 360 MYBP
Lf-Trk1
Lf-Trk2
human TrkA
rat TrkA
chick TrkA
human TrkC
rat TrkC
chick TrkC
zebrafish TrkC2
zebrafish TrkC1
human TrkB
rat TrkB
chick TrkB
zebrafish TrkB2
zebrafish TrkB1
81
100
100
98
100
74
76
100
68
100
74
(c) (d)
Lf-NT
human BDNF
platyfish BDNF
ray BDNF
human NT-4/5
rat NT-4/5
Xl NT-4
human NT-3
chick NT-3
chick NGF
rat NGF
human NGF
platyfish NT-6
carp NT-7
84
100
100
100
57
100
100
100
82
100
65
100
64
platyfish NGF
zebrafish NT-7
ray NT-3
84
Mg-NT
(D. rerio)
Current Opinion in Neurobiology
(NT-4/5)
nb9507.qxd 10/25/1999 8:30 PM Page 617
Furthermore, the phylogenies are in agreement with a sug-
gested hypothesis (called the 2R hypothesis) that two
rounds of tetraploidisation doubled the genome twice early
in chordate and vertebrate history [14,15]. According to
this hypothesis, a first duplication of a single ancestor
would have produced two intermediate neurotrophin
ancestors. A second duplication would then have produced
NGF, NT-3, BDNF, and NT-4/5. This hypothesis also pro-
poses that a trkB ancestor was duplicated, into trkB and a
trkB sister, which was probably lost during evolution
(Figure 1d). However, the phylogenies of several gene
families do not provide support for the 2R hypothesis
[16

], but are more consistent with a single tetraploidisa-

tion and/or duplications of individual genes or
chromosome segments. On the other hand, gene family
phylogenies may be more complex than anticipated, as a
result of tandem duplications, gene conversion, gene
silencing [13

], or biological constraints.
Neurotrophin and Trk receptor genes in
paralogous chromosomal regions
The neurotrophin genes reside on different chromo-
somes. NGF is on human chromosome 1p (HSA 1p),
BDNF on 11p, NT-3 on 12p and NT-4/5 on 19q. A com-
pilation of the maps in the regions of the neurotrophin
genes has shown that several paralogues are located in the
vicinity of the neurotrophin genes (Figure 2a). These
paralogous regions, which have sets of linked genes that
each have linked homologues on another chromosome
[14], argue against random gene duplication as the mech-
anism of formation. Rather, they suggest that the gene
copies were formed at duplication events involving chro-
mosome segments or the entire genome, though the
history of such regions may be complex [13

]. Similar to
the neurotrophin genes, the TrkA, TrkB, and TrkC genes
are located within paralogous regions that contain genes
with homologues in two or more other chromosomes
(Figure 2b). The TrkA, TrkB and TrkC genes are located
on HSA 1q, 9q and 15q (chromosomes 3, 13 and 7 in
mouse). Several translocations and inversions have taken
place since the proposed duplication events. In humans,
the TrkB gene is located on HSA 9q, but the paralogous
region is split on HSA 5p and 9q (Figure 2b), indicating a
translocation; however, in the mouse, this region is con-
tinuous on chromosome 13.
The prime examples of conserved paralogous regions are
in HSA 2q, 7p, 12q, and 17q and their mouse counterparts,
which contain the Hox gene clusters. The four human
chromosomes contain the genes that encode fibrillar colla-
gen, clusters of integrin genes and genes for intermediate
filaments [14,17,18]. A first compilation of the zebrafish
gene map has recently been compared with mammalian
maps [19

]. This comparison revealed conserved chromo-

somal segments. The results corroborate the hypothesis
that major duplication events took place before the diver-
gence of fish and tetrapod lineages. In addition, the results
suggest that chromosome duplications or an extra round of
tetraploidisation could have taken place early in the oste-
ichtyean lineage [19

].
Orthologues, paralogues and ancestors
Homologous genes that are derived by means of speciation
are called orthologues, and if they are formed by gene
duplication, they are called paralogues. NGF, BDNF, NT-3
and NT-4/5 are paralogues. NT-4 was first isolated from
Xenopus laevis [2], and NT-5 was first isolated from rat [20].
Phylogeny (Figure 1a) and biological data clearly show that
NT-4 and NT-5 are orthologues [21]. Although NT-6 and
NT-7 have been suggested to be paralogues [4

,5

], they
are more likely to be orthologues [6

], as indicated by the
phylogeny (Figure 1a) and the fact that they are related to
each other in a similar way as the species from which they
were isolated. They probably resulted from the duplica-
tion of an ancestral fish NGF gene. Zebrafish NGF/NT-7,
as well as trkB1/trkB2 and trkC1/trkC2 [22], were probably
formed at the major duplication event early in the history
of Osteichtyes [19

,23].
The agnathan neurotrophins have the same structural
characteristics as the gnathostome neurotrophins, suggest-
ing that their common ancestral neurotrophin,
arche-neurotrophin, also had these characteristics. A 3D-
fold similar to the one present in NGF has been found in
the invertebrate clotting protein coagulogen isolated from
the horseshoe crab [24,25]. Coagulogen is a cysteine-knot
protein and appears to share similarities also with the
Drosophila protein sptzle [26]. This suggests that the fold-
ing motif of the neurotrophins is older than the vertebrates
and that it was shared with a distant ancestor in common
with coagulogen and other cysteine-knot proteins.
The diversification of receptor tyrosine kinases (RTKs)
[27] and other genes [28

] into several subfamilies seems

to have taken place before the diploblasttriploblast split
[29

]. The recently described molluscan RTK receptor,

designated Ltrk, from the gastropod mollusc Lymnaea stag-
nalis [30

] suggests an early ancestry of the Trk receptor

family. Ltrk has been shown to bind human NT-3 and
reveals some characteristics of the Trk receptors, including
a limited similarity in the transmembrane domain and tyro-
sine kinase domain.
Co-evolution of neurotrophins and Trk
receptors
Phylogeny and gene map data suggest that the formations
of the neurotrophin and Trk receptor gene families are
linked in time. This has facilitated the co-evolution of
neurotrophins and Trk receptors. This co-evolution has
led to increased specificities between certain
receptorligand pairs, enabling the formation of preferred
ligand and receptor interactions. The various factors
involved in determining the specific interactions
between neurotrophins and Trk receptors, as well as
those contributing to the pan-neurotrophin interaction
with the p75 receptor, have been mapped in the
618 Evolution of the nervous system
nb9507.qxd 10/25/1999 8:30 PM Page 618
neurotrophins: loops, hydrophobic patches and charged
clusters of amino acids are important in this regard
[31,32]. The heritage of gene duplication can be traced in
the differential neurotrophins and Trk receptor interac-
tions: NT-3 can bind and activate TrkA [33], although to
a lesser extent than TrkC, and there is no evidence that
interactions between NGF and TrkB or BDNF/NT-4/5
and TrkA serve any function [21,34].
Evolution of expression and function
The nervous system integrates environmental information
and coordinates the organisms adaptive responses, learning
Evolution of the vertebrate neurotrophin and Trk receptor gene families Hallbk 619
Figure 2
Diagram of gene maps depicting paralogous
genes in the region of neurotrophin and Trk
receptor genes on human chromosomes.
(a) Paralogous regions around the
neurotrophin genes on HSA 1p, 11p, 12p and
19q. (b) Paralogous regions around the Trk
receptor genes on HSA 1q, 9q (5p) and 15q.
Members of each gene family are named
according to the Genome Database
nomenclature (http://www.gene.ucl.ac.uk/
nomenclature/). The position of each
paralogous gene in the diagram represents an
estimation based on physical and/or linkage
mapping and is relative on the chromosome.
Locally duplicated genes are placed under
each other. The location of genes in the Trk
paralogous chromosomal region on HSA 19p
suggests tentatively that the TrkB sister was
located in this region. Genes marked with an
asterisk (*) have a position that deviates from
the exact corresponding location but is in the
correct region. Double asterisks (**) indicate
that the location of the gene is on the correct
chromosome but is not determined. The
neurotrophin and Trk paralogues are boxed.
AGC, aggrecan; ALDH, aldehyde
dehydrogenase; ANX, annexin; ARH, Aplysia
ras-related homologue; ATP, Na
+
/K
+
transporting ATPase; CAP, calpain;
CDKN, cyclin-dependent kinase inhibitor;
CRABP, cellular retinoic acid-binding protein;
CSPG, versican; CTS, cathepsin;
FDPSL, farnesyl diphosphate synthase-like
protein; FSHB, follicle stimulating hormone ;
GNA, guanine nucleotide binding protein;
GYS, glycogen synthase; INSR, insulin
receptor; IGF1R, insulin-like growth factor 1
receptor; KCN, K
+
voltage-gated channel;
LDH, lactate dehydrogenase; LHB, luteinizing
hormone ; MAP, microtuble-associated
protein; MEF, MADS box transcription factor
enhancer factor; PACE, paired basic amino
acid cleaving enzyme; PCSK, subtilisin;
PK, pyruvate kinase; PTH, parathyroid
hormone; RAS, viral kinase oncogene
homologue; SIAT, sialyltransferase;
SYT, synaptotagmin; TCF, transcription II;
TFCOUP (ERBAL), transcription factor
COUP; THBS, thrombospondin;
TLE, transducin-like enhancer of split;
TNNT, troponin; TPM, tropomyosin;
TSHB, thyroid stimulating hormone .
HSA 11p
SIAT4 p15
LDHA p15.4
LDHC p15.5-3
HRAS p15.5
ARHG p15.5-4
CDKN1C p15.5
CALCA p15.5-1
CALCB p15.2-1
PTH p15.3-1
TCF13 p15.2
PTPN5 p15.2-1
KCNA9 p15.5-1
KCNC1 p15-1
KCNA4 p14.1-13.4*
SLC1A2 p13-12
BDNF p13
FSHB p13
CAPN1**
HSA 1p
NRAS p13.2
ARH9 p21-13
KCNA3 p13.3
KCNC4 **
NGF p13.1
TSHB p13
ATPA1A p13-11
CAPN2 **
GNAI3 p13
HSA 12p
SIAT8 p11.2-12.1
LDHB p12.1-2
KRAS2 p12.1
CDKN1B p13 *
TCF13L p13.2-3
PTPN6 p13
KCNA1 p13
KCNA5 p13
KCNA6 p13
NTF3 p13 (NT3)
GNAI2 L **
GYS2 p12.2
HSA 19q
GYS1 q13.3
RRAS q13 qt
KCNA7 q13.3
KCNC2 q13.3-4
KCNC3 q13
SLC1A5 q13.3
NTF5 q13.3 (NT4/5)
CAPN4 q**
HSA 19p
TPM4 p13.1
HSA 1q
TPM3 q22-23
NTRK1 q21-22 (TrkA)
CRABP2 q21.3
CTSK q21
CTSS q21
THBS3 q21
PKLR q22
MEF2Dq12-23
INSRR **
HSA 9q
NTRK2 q22.1 (TrkB)
ALDH1 q21
CTSL q21-24
ANX1 q11-12
TLE1 **
HSA 15q
TPM1 q22
NTRK3 q24-25 (TrkC)
ALDH6 q26
CRABP1 q24
CTSH q24-25
THBS1 q15*
TLE3 q22
PKM2 q22
ANX2 q21-22
PCSK6 q26
MEF2A2q26
IGF1R q25-26
TLE2 p13.3
MEF2B p12
INSR p13.2
TPM2 q13
ATPA1A p12-13
LHB q13.3
TNNT3 p15.5 TNNT1 q13.4
TNNI3 q13.2-3
HSA 5p
MEF2Cq14
TFCOUP1 q14 TFCOUP2 q26.1
AGC1 q26.1
PACE q25-26
PCSK5 q21.3
PCSK1 q15-21
CSPG2 q12-14
ERBAL2 **
PCSK4 **
(a) Neurotrophin genes
(b) Trk receptor genes
Current Opinion in Neurobiology
nb9507.qxd 10/25/1999 8:30 PM Page 619
and memory. Experience-dependent changes involving
neuronal selection, survival and plasticity play central
roles in these processes. Thus, genes that drive such
experience-dependent changes are subject to selection.
The neurotrophin and Trk receptor genes are good exam-
ples [35]. Multi-gene families further increase the
selectability and give the potential for a greater diversity
in neuronal regulation. It has repeatedly been shown that
multiple neurotrophin and Trk receptors are beneficial
for the vertebrate organism and function of its nervous
system [1].
One of the hallmarks of neurotrophins is their target-
derived mode of action, which seems to be conserved at
least in the vertebrate subphylum. This is exemplified by
neurotrophin mRNA expression in the inner ear sensory
epithelium of jawless fish [6

], birds [36] and mammals

[37], as it is necessary for afferent innervation [38]. In mam-
malian and bird brains, TrkA, TrkB and TrkC expression is
restricted to specific regions [39], with the expression of
TrkA being more restricted than that of TrkB or TrkC. In
the adult lamprey brain, Lf-trk1 and Lf-trk2 mRNA is
expressed in a general pattern in all regions studied so far
[6

]. The greater resemblance of Lf-Trk expression with

that of TrkB and TrkC suggests that these two Trks have a
more archetypal expression pattern or function compared to
TrkA. This is also in agreement with the higher degree of
conservation of the BDNF and NT-3 sequences during
higher vertebrate evolution [40,41], and with the expres-
sion of TrkB and TrkC but not TrkA in regions of the
reticular formation, which is considered to be an evolution-
arily old part of the vertebrate brain. Furthermore,
lampreys do not have regions (such as sympathetic ganglia,
cortex, hippocampal formation or cholinergic basal fore-
brain nuclei) that are associated with NGFTrkA
expression in higher vertebrates [42]. These regions of the
nervous system evolved after the divergence of jawless fish
and gnatostome lineages, and, consequently, after the
duplication events that gave rise to the NGF:TrkA,
NT-3:TrkC and BDNF/NT-4/5:TrkB gene pairs.
Conclusions
The isolation of lamprey and hagfish neurotrophins has
enabled a phylogenetic analysis of the neurotrophin gene
family, which dates back at least 460 million years to the
early vertebrates. Two gene duplications led to the forma-
tion of NGF, NT-3, BDNF and NT-4/5. NGF and NT-3
were formed by duplication of an intermediate neurotrophin
ancestral gene. BDNF and NT-4/5 were formed by duplica-
tion of another intermediate ancestor. Lamprey Lf-NT is a
descendant of one of these intermediate ancestors. The
duplications took place before the split of cartilaginous fish
but probably after the split of lampreys and hagfish from the
common vertebrate lineage. The analysis of the Trk
sequences shows strikingly similarity with the inferred evo-
lution of the neurotrophins. These results corroborate the
hypothesis suggesting major duplication events, such
as genome doubling by tetraploidisation, prior to the
divergence of the cartilaginous fish. The results also suggest
that the formations of the neurotrophin and Trk gene fami-
lies were linked and that this has permitted neurotrophins
and Trk receptors to co-evolve. These duplications have
also permitted the evolution of differential neurotrophin
and Trk receptor expression, thereby allowing the formation
of specific and different functions in selective neuronal pop-
ulations.
Acknowledgements
I thank Dan Larhammar and Lars-Gustav Lundin for sharing ideas, Klas
Kullander for the work leading to the isolation of Lf-NT, and Alex Mercer
for help with the manuscript. My work is supported by grants from the
Swedish Medical (12187) and Natural Science Research (8904) councils, the
European Commission (CT96-0976), and the Mattsons research fund.
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